Programmable pharmaceutical compositions for chrono drug release

ABSTRACT

The present disclosure provides programmable osmotic-controlled oral compositions providing delayed release of a therapeutically acceptable amount of a drug. The programmable osmotic-controlled compositions of the disclosure provide a lag time that is independent of the presence or absence of food, type of food, pH, gastric emptying, gastric motility, and volume and viscosity of gastric fluid. The compositions of the disclosure can be programmed to provide a desired and precise lag time, and release drug, after the lag time, at a rhythm, e.g., that matches the human circadian rhythm of a condition&#39;s symptoms and/or of the individual being treated in the application of the therapy to optimize therapeutic outcome and minimize side effects.

1. RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/021,124, filed Sep. 15, 2020, which is a continuation of U.S.application Ser. No. 16/809,714 filed Mar. 5, 2020, which is acontinuation-in-part of International Application No. PCT/US2019/020815,filed Mar. 5, 2019, which claims priority to U.S. Provisional PatentApplication Nos. 62/638,667, filed Mar. 5, 2018, and 62/760,771, filedNov. 13, 2018, the disclosures of which are hereby incorporated byreference herein in their entireties.

2. TECHNICAL FIELD

The presently disclosed subject matter relates to programmableosmotic-controlled oral compositions providing delayed controlledrelease of a drug. The osmotic-controlled oral compositions of thedisclosure can be programmed to provide a desired and precise lag time,thereby releasing drug, after the lag time, at a rhythm, e.g., thatmatches the human circadian rhythm of a condition's symptoms and/or ofthe individual being treated in the application of the therapy, tooptimize therapeutic outcome and minimize side effects. Theosmotic-controlled oral compositions of the disclosure can be programmedto provide a desired and precise lag time, and a desired release profileafter the lag time to provide therapeutic plasma concentrations ofdrugs, even while releasing the drugs in the lower portions of the GItract. The programmable osmotic-controlled compositions of thedisclosure can provide a lag time that is substantially independent ofthe presence or absence of food, type of food, pH, gastric emptying, andvolume and viscosity of immediate microenvironment of drug release.

3. BACKGROUND

Attention deficit disorders, e.g., ADHD, are among the most commondevelopmental disorders in children and are characterized by symptomssuch as impulsiveness, hyperactivity, and inattentiveness. Hyperactivityis common in children with ADHD. Stimulant medications are widely usedas a pharmacological treatment for ADHD/ADD. Stimulant medicationsapproved by the FDA include methylphenidate, and salts and isomers ofamphetamine. One major challenge of treating ADHD and otherstimulant-responsive conditions is delivering and maintaining aneffective stimulant concentration in patients, particularly children,throughout the day, in particular during the morning hours whencognitive abilities and concentration are needed for school, work, orextracurricular activities, and during the late afternoon or eveningwhen students often do homework. Early morning symptom control,including getting the children ready for school, is a major challengefor parents and caregivers of children suffering from ADHD/ADD.Typically, stimulant-based medications are dosed two hours prior tobeginning an early morning routine, with an onset of treatment effectusually about two hours after administration. Such medications requiretwice-daily administration and cause compliance issues. JORNAY PM™, acommercially available product of methylphenidate (IronshorePharmaceuticals and Development Inc., NDA #209311), has been approved bythe FDA for the treatment of ADHD in patients six years and older.JORNAY PM™ is a methylphenidate formulation that is to be administeredin the evening in an attempt to improve ADHD symptoms in the earlymorning and throughout the day. However, drug release from theformulation can be affected by pH, food, and gastric transit time, witha potential for variable drug release during the night and predawnhours, leading to insomnia.

Extended release of a drug from an oral dosage form can be affected byhydrodynamic conditions in the GI tract that are associated with, e.g.,pH and presence of food in the stomach. Osmotic-controlled oral drugdelivery systems (OROS) known in the art provide controlled extendedrelease of a drug with zero-order kinetics. The OROS drug deliverysystem is an advanced drug delivery technology that uses osmoticpressure as a driving force for controlled delivery of active agents.Such systems provide a constant release rate of a drug over an extendedperiod of time. OROS delivery systems utilize osmotic pressure togenerate a driving force for imbibing fluid into a compartment enclosedpartially or completely by a semipermeable membrane that permits freediffusion of a fluid but not solutes, including active or osmoticagents.

Osmotic-controlled compositions comprising a drug in a mixture withosmotically active agents/osmotic agents are known in the art (e.g.,U.S. Pat. Nos. 4,327,725; 4,612,008; 4,783,337; 5,082,668). Thesecompositions comprise a bilayer tablet core surrounded by asemipermeable membrane with an orifice. The first component layer, thepull layer, comprises a drug(s) in a mixture of excipients that forms adeliverable drug formulation within the compartment. A second componentlayer, the push layer, comprises osmotic agents, e.g., swellablehydrophilic polymers and osmogens. The swellable hydrophilic polymers inthe second component layer comprise one or more high molecular weighthydrophilic polymers that swell as fluid is imbibed. The secondcomponent layer is referred to as “push layer” because as fluid isimbibed, the hydrophilic polymer swells and pushes against thedeliverable drug formulation in the first component layer, therebyfacilitating release of drug formulation from the first layer through anorifice in the semipermeable membrane at a substantially constant rate.

Although suitable for providing a controlled release of drugs withvarious solubilities, osmotic-controlled compositions known in the artare not entirely suitable for being programmed as controlled releasecompositions that 1) delay the release of a drug/provide a lag time forat least about 3 hours, 2) provide a lag time that is independent of thepresence or absence of food, type of food, pH, gastric emptying, andvolume of gastric fluid, 3) provide a plasma concentration of the activepharmaceutical ingredient during the lag time that is less than about20% of a maximum concentration (C_(max)), 4) provide pH-independent drugrelease, after the lag time, at a rhythm that matches the humancircadian rhythm of a condition's symptoms and/or of the individualbeing treated in the application of the therapy, and 5) provide adesired bioavailability and complete drug recovery at a desired time. Atypical osmotic-controlled system known in the art provides a short lagtime of about 30-120 minutes during which the system hydrates beforezero-order delivery from the system is obtained.

For at least these reasons, there remains a need to developosmotic-controlled systems that can provide controlled release of a drugat a desired rate and time, while providing complete drug recovery.There remains a need to develop compositions that can be programmed fortreating conditions that require delayed controlled release of a drug,e.g., compositions for treating central nervous system (CNS) disorders,asthma, arthritis, congestive heart failure, myocardial infarction,stroke, cancer, peptic ulcer, narcolepsy, epilepsy, migraine, pain,etc., wherein the risk and symptoms of the disease vary predictably overtime.

The present disclosure addresses the above-mentioned unmet needs in theart by providing osmotic-controlled, oral delayed release compositionsthat can improve the symptoms of a disease in the early morning andthroughout the day, or in a pulsatile manner, without the need for earlymorning dosing that requires an onset time of about two hours. Suchcompositions address the long-felt need of providing food-independentdelayed release that can avoid burdensome early morning dosing and canbe programmed to provide a desired and precise lag time, therebyreleasing drug, after the lag time, at a rhythm, e.g., that matches thehuman circadian rhythm of a condition's symptoms and/or of theindividual being treated in the application of the therapy, to optimizetherapeutic outcome and minimize side effects. The compositions of thedisclosure provide a precise lag time that is independent of thepresence or absence of food, type of food, pH, gastric emptying, gastrictransit time, and volume of fluid in the immediate microenvironment ofdrug release. In particular, the osmotic-controlled, oral, delayedrelease compositions of the disclosure provide desired drugbioavailability while releasing the drug in lower portions of the GItract, e.g., colon, with viscous alkaline microenvironment. Theosmotic-controlled oral compositions of the disclosure are designed toprovide minimal variability in drug release among tablets.

4. SUMMARY

The foregoing has outlined broadly the features and technical advantagesof the present application in order that the detailed description thatfollows may be better understood. Additional features and advantages ofthe application will be described hereinafter which form the subject ofthe claims of the application. It should be appreciated by those skilledin the art that the conception and specific embodiment disclosed may bereadily utilized as a basis for modifying or designing other structuresfor carrying out the same purposes of the present application. It shouldalso be realized by those skilled in the art that such equivalentconstructions do not depart from the spirit and scope of the applicationas set forth in the appended claims. The novel features which arebelieved to be characteristic of the application, both as to itsorganization and method of operation, together with further objects andadvantages will be better understood from the following description.

To achieve these advantages and in accordance with the purpose of thedisclosed subject matter, as embodied and broadly described subjectmatter includes an osmotic-controlled oral pharmaceutical compositionproviding delayed release of a therapeutically effective amount a drug,the composition including a multilayer core including an active layersandwiched between a placebo layer and a push layer, wherein the placebolayer includes at least one polyethylene oxide polymer having an averagemolecular weight of from about 300,000 Da to about 900,000 Da; theactive layer includes a drug, at least one polyethylene oxide polymerhaving a molecular weight of from about 100,000 Da to about 600,000 Da;the push layer includes at least one polyethylene oxide polymer havingan average molecular weight of greater than or equal to 1000,000 Da, andat least one osmogen; and a semipermeable membrane surrounding themultilayer core, wherein the semipermeable membrane is present in anamount of from about 1 wt % to about 20 wt % coating weight gain, basedon the total weight of the multilayer core. In certain embodiments, thesemipermeable membrane includes at least one orifice facing the placebolayer. In certain embodiments, the orifice has an optimum orificediameter of from about 0.6 mm to about 2.0 mm. In certain embodiments,the placebo layer is present in an amount of from about 10 wt % to about50 wt %, based on the total weight of the multilayer core. In certainembodiments, the active layer contains a drug:polyethylene oxide polymerratio of between about 20:80 and about 80:20 by weight. In certainembodiments, the osmogen in the push layer is present in an amount offrom about 5 w % to about 30 wt %, based on total weight of the pushlayer.

In certain embodiments, the composition provides a lag time of at leastabout 3 hours, during which the composition releases no more than 20 wt% of the drug.

In certain embodiments, the composition exhibits not more than 30%variability in the lag time with variations in pH, viscosity, and volumeof a dissolution medium.

In certain embodiments, the lag time does not depend upon gastricmotility and presence of food in the GI tract.

In certain embodiments, the semipermeable membrane includes apH-independent water-insoluble polymer and a pH-independent pore formerat a polymer to pore former ratio of between about 80:20 and about99.5:0.5 by weight.

In certain embodiments, the semipermeable membrane includes apH-independent water-insoluble polymer and a pH-independent pore formerat a polymer to pore former ratio of between about 90:10 and about 95:5by weight.

In certain embodiments, the pH-independent water-insoluble polymer isselected from the group consisting of cellulose acetate, celluloseacetate butyrate, and cellulose triacetate.

In certain embodiments, the pH-independent pore former is selected fromthe group consisting of polyethylene glycol, hydroxypropyl cellulose,polyvinyl pyrolidone, polyvinyl acetate, mannitol, and methyl cellulose,poloxamer, triethyl citrate, triacetin, hydroxypropyl methylcellulose,glycerol, and combinations thereof.

In certain embodiments, the semipermeable membrane further includes atleast one plasticizer selected from the group consisting of polyethyleneglycols, triethyl citrate, triacetin, diethyl tartrate, dibutylsebacate, and combinations thereof.

In certain embodiments, the polyethylene oxide polymer in the push layerhas an average molecular weight of about 1000,000 Da, about 2000,000 Da,about 4000,000 Da, about 5000,000 Da, about 7000,000 Da, or intermediatevalues therein.

In certain embodiments, the placebo layer further comprises a wickingagent selected from the group consisting of croscarmellose sodium,calcium carboxymethyl cellulose, crospovidone, low-substitutedhydroxypropyl celluloses, sodium starch glycolate, colloidal silicondioxide, alginic acid and alginates, acrylic acid derivatives, andvarious starches.

In certain embodiments, the placebo layer further comprises an osmogenselected from the group consisting of sodium chloride, potassiumchloride, potassium sulfate, lithium sulfate, sodium sulfate, lactoseand sucrose combination, lactose and dextrose combination, sucrose,dextrose, mannitol, dibasic sodium phosphate, and combinations thereof.

In certain embodiments, the placebo layer further comprises a wickingagent and an osmogen.

In certain embodiments, the composition further comprises an immediaterelease drug layer over the semipermeable membrane, wherein theimmediate release drug layer contains a drug that is similar to the drugin the active layer.

In certain embodiments, the composition further comprises an immediaterelease drug layer over the semipermeable membrane, wherein theimmediate release drug layer contains a drug that is different from thedrug contained in the active layer.

In certain embodiments, the present disclosure provides anosmotic-controlled oral pharmaceutical composition providing animmediate release of a therapeutically effective amount of a drug and adelayed release of a therapeutically effective amount of the same or adifferent drug, the composition including a multilayer core including anactive layer sandwiched between a placebo layer and a push layer,wherein the placebo layer includes at least one polyethylene oxidepolymer having an average molecular weight of from about 300,000 Da toabout 900,000 Da; the active layer includes a drug, at least onepolyethylene oxide polymer having a molecular weight of from about100,000 Da to about 600,000 Da; the push layer includes at least onepolyethylene oxide polymer having an average molecular weight of greaterthan or equal to 1000,000 Da, and at least one osmogen; a semipermeablemembrane surrounding the multilayer core; and an immediate release druglayer surrounding the semipermeable membrane. The immediate release druglayer comprises at least one drug for immediate release. In certainembodiments, the semipermeable membrane is present in an amount of fromabout 1 wt % to about 20 wt % coating weight gain, based on the totalweight of the multilayer core. In certain embodiments, the semipermeablemembrane includes at least one orifice facing the placebo layer. Incertain embodiments, the orifice has an optimum orifice diameter of fromabout 0.6 mm to about 2.0 mm. In certain embodiments, the placebo layeris present in an amount of from about 10 wt % to about 50 wt %, based onthe total weight of the multilayer core. In certain embodiments, theactive layer contains the drug and polyethylene oxide polymer in a ratioof between about 20:80 and about 80:20 by weight. In certainembodiments, the osmogen in the push layer is present in an amount offrom about 5 w % to about 30 wt %, based on total weight of the pushlayer.

In certain embodiments, the drug for immediate release is a sedativeselected from the group consisting of clonidine, guanfacine,diphenhydramine, melatonin, and pharmaceutically acceptable saltsthereof.

In certain embodiments, the drug for delayed release is selected fromthe group consisting of methylphenidate, mixed amphetamines,armodafinil, hydrocortisone, and pharmaceutically acceptable saltsthereof.

In certain embodiments, the drug for immediate release is a sedative andthe drug for delayed release is a stimulant. In certain embodiments, thedelayed release is a delayed extended release and the compositionprovides immediate release of the sedative, a lag time of at least about6 hours during which the composition releases no more than 10% ofstimulant, and a delayed extended release of the stimulant.

In certain embodiments, the disclosure provides an osmotic-controlledoral pharmaceutical composition providing pulsatile release of atherapeutically effective amount of one or more drugs, the compositionincluding a multilayer core and a semipermeable membrane over themultilayer core. The multilayer core includes layers in the followingorder: a first placebo layer containing at least one polyethylene oxidepolymer having an average molecular weight of from about 300,000 Da toabout 900,000 Da; a first active layer containing a first drug and atleast one polyethylene oxide polymer having an average molecular weightfrom about 300,000 Da to about 900,000 Da; a second placebo layercontaining at least one polyethylene oxide polymer having an averagemolecular weight of from about 300,000 Da to about 900,000 Da; a secondactive layer containing a second drug and at least one polyethyleneoxide polymer having an average molecular weight from about 300,000 Dato about 900,000 Da; and a push layer containing at least onepolyethylene oxide polymer having an average molecular weight of greaterthan or equal to 1000,000 Da, and at least one osmogen. In certainembodiments, the semipermeable membrane is present in an amount of fromabout 1 wt % to about 20 wt % coating weight gain, based on the totalweight of the multilayer core. In certain embodiments, the semipermeablemembrane includes at least one orifice facing the placebo layer. Incertain embodiments, the orifice has an optimum orifice diameter of fromabout 0.6 mm to about 2.0 mm. In certain embodiments, each of the firstand the second placebo layer is present in an amount of from about 10 wt% to about 50 wt %, based on the total weight of the multilayer core. Incertain embodiments, each of the first active layer and the secondactive layer contains a drug:polyethylene oxide polymer ratio of betweenabout 20:80 and about 80:20 by weight. In certain embodiments, theosmogen in the push layer is present in an amount of from about 5 w % toabout 30 wt %, based on total weight of the push layer. In certainembodiments, the pulsatile release comprises a delayed release of afirst pulse containing the first drug, a lag time, and a second pulsecontaining the second drug.

In certain embodiment, the first drug and the second drug are same. Incertain embodiments, the composition further comprises an immediaterelease drug layer over the semipermeable membrane, wherein theimmediate release drug layer contains a third drug. In certainembodiments, the third drug is different from the first drug and thesecond drug.

In certain embodiments, the disclosure provides an osmotic-controlledoral pharmaceutical composition providing pulsatile release of atherapeutically effective amount of one or more drugs, the compositionincluding a multilayer core and a semipermeable membrane over themultilayer core. The multilayer core includes layers in the followingorder: a first active layer containing a first drug and at least onepolyethylene oxide polymer having an average molecular weight from about300,000 Da to about 900,000 Da; a first placebo layer containing atleast one polyethylene oxide polymer having an average molecular weightof from about 300,000 Da to about 900,000 Da; a second active layercontaining a second drug and at least one polyethylene oxide polymerhaving an average molecular weight from about 300,000 Da to about900,000 Da; a second placebo layer containing at least one polyethyleneoxide polymer having an average molecular weight of from about 300,000Da to about 900,000 Da; and a push layer containing at least onepolyethylene oxide polymer having an average molecular weight of greaterthan or equal to 1000,000 Da, and at least one osmogen. In certainembodiments, the semipermeable membrane is present in an amount of fromabout 1 wt % to about 20 wt % coating weight gain, based on the totalweight of the multilayer core. In certain embodiments, the semipermeablemembrane includes at least one orifice facing the active layer. Incertain embodiments, the orifice has an optimum orifice diameter of fromabout 0.6 mm to about 2.0 mm. In certain embodiments, each of the firstand the second placebo layer is present in an amount of from about 10 wt% to about 50 wt %, based on the total weight of the multilayer core. Incertain embodiments, each of the first active layer and the secondactive layer contains a drug:polyethylene oxide polymer ratio of betweenabout 20:80 and about 80:20 by weight. In certain embodiments, theosmogen in the push layer is present in an amount of from about 5 w % toabout 30 wt %, based on total weight of the push layer. In certainembodiments, the pulsatile release comprises release of a first pulsecontaining the first drug, a lag time, and a second pulse containing thesecond drug.

5. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a cross-section view of a four-layer osmotic dosage formcomprising an IR clonidine coating; a cellulose acetate coatingcontaining an orifice, placed below the clonidine IR coating; a placebolayer facing the orifice; a delayed immediate release layer, containingmethylphenidate or a pharmaceutically acceptable salt thereof, placedbelow the placebo layer; a delayed extended release layer, containingmethylphenidate or a pharmaceutically acceptable salt thereof, placedbelow the delayed immediate release layer; and a push layer placed belowthe delayed extended release layer.

FIG. 2 depicts a cross-section view of a three-layer osmotic dosage formcomprising a cellulose acetate coating containing an orifice; a placebolayer facing the orifice; a delayed extended release layer, containingmethylphenidate or a pharmaceutically acceptable salt thereof, placedbelow the placebo layer; and a push layer placed below the delayedextended release layer.

FIG. 3 depicts a cross-section view of a three-layer osmotic dosage formcomprising an IR clonidine coating; a cellulose acetate coatingcontaining an orifice, placed below the clonidine IR coating; a placebolayer facing the orifice; a delayed extended release layer containingmethylphenidate or a pharmaceutically acceptable salt thereof, placedbelow the placebo layer; and a push layer placed below the delayedextended release layer.

FIG. 4 depicts a cross-section view of a three-layer osmotic dosage formcomprising an IR clonidine coating; a cellulose acetate coatingcontaining an orifice, placed below the clonidine IR coating; a placebolayer containing small amounts of a drug for immediate release andfacing the orifice; a delayed extended release layer, containingmethylphenidate or a pharmaceutically acceptable salt thereof, placedbelow the placebo layer; and a push layer placed below the delayedextended release layer.

FIG. 5 depicts a cross-section view of a three-layer osmotic dosage formcomprising an IR clonidine coating; a seal coating below the IRclonidine coating; a clonidine ER coating below the seal coating; acellulose acetate coating containing an orifice, placed below the ERclonidine coating; a placebo layer facing the orifice; a delayedextended release layer containing methylphenidate or a pharmaceuticallyacceptable salt thereof, placed below the placebo layer; and a pushlayer placed below the delayed extended release layer.

FIG. 6 depicts a cross-section view of a five-layer osmotic dosage formcomprising an IR coating containing a drug for IR, a cellulose acetatecoating containing an orifice below the IR coating, a first placebolayer facing the orifice, a first IR drug layer below the first placebolayer, a second placebo layer below the first IR drug layer, a second IRdrug layer below the second placebo layer, and a push layer placed belowthe second IR drug layer and facing away from the orifice.

FIG. 7 shows the effect of the amount of placebo layer amount ondissolution profile of Tablets 20 and 21, placed in about 900 ml ofabout 0.01N HCl, using USP II (sinkers) at about 50 rpm and about 37° C.Percent drug dissolved is plotted over time (hours). Tablet 20 contains150 mg of POLYOX® WSR 1105 in the placebo layer; and Tablet 21 contains75.0 mg of POLYOX® WSR 1105 in the placebo layer. Tablet 20 containsabout 34 wt % of placebo layer, based on the total weight of theuncoated tablet core. Tablet 21 contains about 20 wt % of placebo layer,based on the total weight of the uncoated tablet core. Tablets 20 and 21contain 15 wt % of coating, based on the total weight of the uncoatedtablet core. The figure demonstrates that tablets with higher amount ofplacebo layer exhibit higher dissolution rate and higher drug recoverycompared to tablets with lesser amounts of placebo layer. The figurefurther demonstrates that the POLYOX® WSR 1105 amount in the placebolayer, and weight % of placebo layer, based on the total weight of theuncoated tablet core, does not affect lag time.

FIG. 8 shows the effect of average molecular weight of the POLYOX®,present in the placebo layer, on dissolution profile of the tablets 20and 22, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percent drugdissolved is plotted over time (hours). Tablet 20 contains POLYOX® WSR1105, and Tablet 22 contains POLYOX® 205 in the placebo layer. TheFigure demonstrates an improvement in dissolution rate and reduction indrug recovery, and no change in lag time, with increasing the averagemolecular weight of POLYOX®, present in the placebo layer, from about600K (POLYOX® 205) to about 900K (POLYOX® 1105).

FIG. 9 shows the effect of drug:polymer weight ratio on lag time anddrug recovery of Tablets 23 and 24, placed in about 900 ml of about0.01N HCl for up to 24 hours, using USP Apparatus II (Sinkers), at 50rpm and 37° C. Percent drug dissolved is plotted over time (hours).Tablet 24 containing a drug to polymer weight ratio of about 30:70provides a lag time of about 9 hours, Tablet 23 containing a drug topolymer weight ratio of about 20:80 provides a lag time of about 10hours. The figure demonstrates that increasing drug:polymer weight ratioin the active layer reduces lag time. The figure further demonstratesthat tablets with the drug to polymer weight ratio of about 30:70provide higher drug recovery compared to tablets with drug to polymerweight ratio of about 20:80.

FIG. 10 shows the effect of presence of sodium chloride in the activelayer on dissolution profile of Tablets 25 and 26, placed in about 900ml of about 0.01N HCl using USP Apparatus II (Sinkers), at 50 rpm and37° C. Percent drug dissolved is plotted over time (hours). Tablet 25contains sodium chloride in the active layer and Tablet 26 does notcontain sodium chloride in the active layer. The figure demonstratesthat Tablet 25 containing NaCl in the active layer exhibits higher drugrecovery compared to Tablet 26 containing no amount of sodium chloridein the active layer.

FIG. 11 shows the effect of presence of sodium chloride in the pushlayer on dissolution profile of Tablets 24, 27, 28, and 29, placed inabout 900 ml of about 0.01N HCl for up to 24 hours, using USP ApparatusII (Sinkers), at 50 rpm and 37° C. Percent drug dissolved is plottedover time (hours). The figure demonstrates that the presence of sodiumchloride in the push layer reduces lag time and improves release rateand drug recovery at 24 hours. The figure further demonstrates thatincreasing the amount of sodium chloride in the push layer reduces lagtime.

FIG. 12 shows the effect of CA to PEG ratio in the membrane on lag timeand drug recovery of the Tablets 30 and 31, with 15% coating weightgain, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percent drugdissolved is plotted over time (hours). The Figure demonstrates thatincreasing amount of cellulose acetate in the membrane increases lagtime and reduces drug recovery from the membrane coated tablets.

FIG. 13 shows the effect of coating weight gain, and presence of sodiumchloride in the active layer, on lag time and drug recovery of Tablets32, 32A, 33, and 34, placed in about 900 ml of about 0.01N HCl for up to24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentdrug dissolved is plotted over time (hours). The Figure demonstratesthat the tablet with a higher coating level (Tablet 32A) exhibitsreduced drug recovery and increased lag time compared to Tablet 32. TheFigure further compares drug recovery between coated tablets at samecoating weight gain, with and without sodium chloride in active layer.The Figure demonstrates that tablets containing sodium chloride inactive layer exhibit improved drug recovery compared to tablets withoutsodium chloride in the active layer, both tablets at a same coatingweight gain. The Figure further shows that a decrease in amount ofPOLYOX® 205 in placebo layer improves drug recovery.

FIG. 14 shows the effect of average molecular weight of the POLYOX®present in the placebo layer on lag time and drug recovery of Tablets35, 36, and 37, placed in about 900 ml of about 0.01N HCl for up to 24hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentdrug dissolved is plotted over time (hours). The figure demonstratesthat Tablet 35 containing POLYOX® 205 in the placebo layer and 20 mg ofsodium chloride in the active layer provide shorter lag time compared toTablet 36 containing POLYOX® 1105 in the placebo layer and 10 mg od NaClin the active layer. The figure further demonstrates that for Tabletscontaining POLYOX® 205 in the placebo layer, the tablets with highersodium chloride amount in active layer and less coating weight gain(Tablet 35) provide shorter lag time compared to tablets containinghigher coating level and less amount of sodium chloride in the activelayer (Tablet 36).

FIG. 15 shows the effect of push layer amount on lag time of Tablets 38and 39, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percent drugdissolved is plotted over time (hours). The Figure demonstrates that fortablets containing POLYOX® 205 in the placebo layer, the lag timedecreases with increase in push layer amount from about 17 wt % to about22 wt %, based on the total weight of the uncoated trilayer tablet.

FIG. 16 shows the effect of pH on lag time of Tablet 40, placed in about900 ml of about 0.01N HCl, in pH 4.5 acetate buffer, and in pH 6.8phosphate buffer. Percent drug dissolved is plotted over time (hours).The Figure demonstrates that lag time is independent of the pH of thedissolution medium.

FIG. 17 shows the effect of the push layer amount on lag time in Tablets41 and 42, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentage drugdissolved is plotted over time (hours). The figure demonstrates that fortablets containing POLYOX® 1105 in the placebo layer and with adrug:polymer weight ratio of about 40:60 in the active layer, anincrease in push layer amount, from about 26 wt % to about 28 wt %,based on the total weight of the uncoated tablet core, improves drugrecovery without affecting the lag time.

FIG. 18 shows effect of polymer amount in the placebo layer and coatingweight gain/coating level on lag time of Tablets 43 and 44, containing adrug:polymer weight ratio of about 40:60, placed in about 900 ml ofabout 0.01N HCl for up to 24 hours, using USP Apparatus II (Sinkers), at50 rpm and 37° C. Percentage drug dissolved is plotted over time(hours). The Figure demonstrates that higher placebo layer amounts andhigher coating level on tablet increases lag time.

FIG. 19 shows the effect of pH on lag time of Tablet 40, placed in about900 ml of about 0.01N HCl, pH 4.5 acetate buffer, and in pH 6.8phosphate buffer. Percent drug dissolved is plotted over time (hours).The figure demonstrates that there is no substantial change in lag timewith changing pH of the dissolution medium.

FIG. 20 shows the effect of viscosity of the dissolution medium on lagtime of Tablet 45, placed in dissolution mediums with differentviscosities, e.g., with and without HPMC. Percent dissolved is plottedover time (hours). The Figure demonstrates there is no substantialchange in lag time with changing viscosity of the dissolution medium.

FIG. 21 shows the effect of changing hydrodynamics of the dissolutionmedium on lag time of Tablet 45, placed in about 900 ml of about 0.01NHCl for up to 24 hours, using USP Apparatus II (Sinkers), at 50 rpm and37° C. Percentage drug dissolved is plotted over time (hours). Tablet 45contains a drug:polymer weight ratio of about 40:60. The Figuredemonstrates that there is no substantial change in lag time withchanging hydrodynamics of the dissolution medium.

FIG. 22 shows effect of sodium chloride in placebo layer on lag time ofTablets 44, 46, and 47, placed in about 900 ml of about 0.01N HCl oftablets for up to 24 hours, using USP Apparatus II (Sinkers), at 50 rpmand 37° C. Percentage drug dissolved is plotted over time (hours).Tablet 44 contains 0% sodium chloride, Tablet 46 contains about 5%sodium chloride, and Tablet 47 contains about 10% sodium chloride in theplacebo layer, based on the total weight of the placebo layer. TheFigure demonstrates that presence of sodium chloride in placebo layerhas negligible effect on lag time and release rate.

FIG. 23 shows the effect of POLYOX® grade in placebo layer on lag timeof Tablets 44, 48, and 49, placed in about 900 ml of about 0.01N HCl forup to 24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C.Percentage drug dissolved is plotted over time (hours). Tablet 44contains POLYOX® 1105 in the placebo layer; Tablet 48 contains POLYOX®N750 in the placebo layer; and Tablet 49 contains POLYOX® N80 in theplacebo layer. The Figure demonstrates that the average molecular weightof POLYOX® in the placebo layer should be at least about 300K to providea lag time of at least about 6 hours.

FIG. 24 shows the effect of POLYOX® grade/average molecular weight inpush layer on release rate and drug recovery of Tablets 44, 50, and 51,placed in about 900 ml of about 0.01N HCl for up to 24 hours, using USPApparatus II (Sinkers), at 50 rpm and 37° C. Percentage drug dissolvedis plotted over time (hours). The figure compares release rate and drugrecovery in compositions containing POLYOX® WSR 303 (7M), POLYOX® WSR301 (3M), and POLYOX® WSR Coagulant (5M) in push layer. The figuredemonstrates that compositions containing POLYOX® N750 in the placebolayer and POLYOX® WSR 301 in the push layer or compositions containingPOLYOX® N80 in the placebo layer and POLYOX® WSR Coagulant in the pushlayer provide higher drug recovery, compared to compositions containingPOLYOX® 1105 in the placebo layer and POLYOX® WSR 303 in the push layer.

FIG. 25 shows the effect of the presence of a wicking agent and anosmogen in the placebo layer on lag time of Tablets 52 and 53, placed inabout 900 ml of about 0.01N HCl, using USP Apparatus II (Sinkers), at 50rpm and 37° C. Percentage drug dissolved is plotted over time (hours).The Figure demonstrates that addition of a wicking agent and sodiumchloride in the placebo layer reduces the drug recovery withoutsubstantially affecting lag time.

FIG. 26 provides dissolution profiles of Tablets 54, 57, and 58 in 5 mlof pH 6.8 buffer, using USP Apparatus II (Sinkers), at 5 rpm and 37° C.(low-volume, low-RPM condition). FIG. 26 demonstrates that Tablet 54,with about 10% coating weight gain, provides an improved release rateand improved drug recovery compared to Tablets 57 and 58, with about12.5% coating weight gain. FIG. 26 further demonstrates that tabletswith higher amount of pore former (Polyethylene glycol present inOPADRY® CA clear (90:10)) in the coating layer (e.g., Tablet 57),provide faster drug release compared to tablets containing less amountof pore former in OPADRY® CA clear (95:5) in the coating layer (e.g.,Tablet 58), at a same coating weight gain. FIG. 26 also demonstratesthat tablets containing POLYOX® 1105 in placebo layer and POLYOX® WSR303 in push layer (Tablet 58) provided longer lag time compared totablets containing POLYOX® 205 in placebo layer and POLYOX® WSRcoagulant in the push layer (Tablets 54 and 57).

FIG. 27 compares pharmacokinetic performance of extended releasecompositions of the disclosure with marketed extended releasemethylphenidate product. FIG. 27 demonstrates that the compositions ofthe disclosure provide a lag time of about 7 hours and a C_(max) ofabout 22 ng at 12 hours post administration.

6. DETAILED DESCRIPTION

The present disclosure is directed to delayed release methylphenidatecompositions, amongst other things.

6.1. Definitions

The terms used in this specification generally have their ordinarymeanings in the art, within the context of this subject matter and inthe specific context where each term is used. Certain terms are definedbelow to provide additional guidance in describing the compositions andmethods of the disclosed subject matter and how to make and use them.

The terminology used in the present disclosure is for the purpose ofdescribing particular embodiments only and is not intended to belimiting.

As used herein, the use of the word “a” or “an” when used in conjunctionwith the term “comprising” in the claims and/or when used in thespecification can mean “one,” but it is also consistent with the meaningof “one or more,” “at least one,” and “one or more than one.” Stillfurther, the terms “having,” “including,” “containing,” and “comprising”are interchangeable, and one of skill in the art is cognizant that theseterms are open-ended terms.

As used herein, “and/or” refers to and encompasses any and all possiblecombinations of one or more of the associated listed items.

The term “about” or “approximately” means within an acceptable errorrange for the particular value as determined by one of ordinary skill inthe art, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean within 3 or more than 3 standard deviations,per the practice in the art. Alternatively, “about” can mean a range ofup to 20%, up to 15%, up to 10%, up to 5%, up to 1%, up to 0.5%, or evenup to 0.1% of a given value.

As used herein, a “therapeutically effective,” “therapeutic,” or“therapeutically acceptable” amount refers to an amount that will elicita therapeutically useful response in a subject and includes anadditional amount or overage of active ingredient deemed necessary inthe formulation to provide the desired amount upon administration. Thetherapeutically useful response can provide some alleviation,mitigation, and/or decrease in at least one clinical symptom in thesubject. Those skilled in the art will appreciate that thetherapeutically useful response need not be complete or curative, aslong as some benefit is provided to the subject.

As used herein, the term “drug recovery” refers to percentage of thetotal amount of drug present in the dosage form that is released in adissolution medium. The term “complete drug recovery” refers to releaseof about 90% to about 105% of the drug present in the dosage form.

The term “bioavailability” refers to the fraction of an administereddose of unchanged drug that reaches the systemic circulation.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, and/or inhibiting theprogress of a disease or disorder as described herein. In someembodiments, treatment can be administered after one or more symptomshave developed. In other embodiments, treatment can be administered inthe absence of symptoms. For example, treatment can be administered to asusceptible individual prior to the onset of symptoms (e.g., in light ofa history of symptoms and/or in light of genetic or other susceptibilityfactors). Treatment can also be continued after symptoms have resolved,for example to prevent or delay their recurrence.

The term “chrono release” refers to drug release in a sequential orderof time. In particular, the term “chrono release” means timed orprogrammed release of one or more drugs at a rhythm that matches thehuman circadian rhythm of a condition's symptoms and/or of theindividual being treated in the application of the therapy to optimizethe therapeutic outcome and minimize side effects. In certainembodiments, the term “chrono release” comprises immediate release of adrug followed by an extended release of the same or different drug.

The term “pulsatile release” means rapid release of discrete portions ofdrug in pulses that are separated by a well-defined lag time(s).

The term “lag time” means the time for which release of a drug isdelayed from the time of administration/ingestion of the composition.Not more than about 20% of the maximum plasma concentration (C_(max)) ofthe drug is released during the lag time.

The term “release rate” refers to the quantity of drug released per unittime, e.g., mg of drug released per hour (mg/hour), from a dosage form.Drug release rates are calculated under in vitro dosage form dissolutiontesting conditions known in the art.

The term “delayed release” means release of a discrete portion(s) of adrug at a time(s) other than immediately after administration/ingestion.

The term “immediate release” means substantially complete release of adrug within a time period of about 1 hour or less, preferably within 30minutes or less, post-administration.

The term “immediate release drug layer” means an immediate releasecoating layer comprising a drug and at least one pharmaceuticallyacceptable carrier. The immediate release drug layer dissolves rapidlyupon administration and provides an immediate release dose of the drug.

The term “controlled release” means drug release that is controlled toalter the timing and/or rate of release of the drug substance from thatof a conventional immediate release dosage form. The controlled releasedosage forms of the disclosure can include modified release dosage formsproviding delayed release (DR), extended release (ER), target release(TR), pulsatile release, chrono release, or any combination thereof, ofdrug substance.

The term “extended release” refers to modified release dosage forms orcompositions that are formulated to allow the drug to be available overan extended period of time after administration, thereby allowing areduction in dosing frequency, as compared to a drug presented as animmediate release dosage form.

The terms “gastric medium,” “simulated gastric fluid,” “simulatedintestinal fluid,” “intestinal medium,” and the like, as used herein,refer to media occurring in stomach and in intestines, correspondingly,or to the solutions that are used to mimic their chemical environment invitro.

As used herein, the term “dissolution medium” refers to a medium used tomimic pH of gastric fluid in fed or fasted state of an individual. Incertain embodiments, the medium used to mimic fed state of an individualincludes pH 6.8 acetate buffer; and the medium used to mimic fastedstate of an individual includes 0.01 N HCl.

The term “solubility” is defined in terms of ability to dissolve inwater. The term “highly soluble” includes drugs with a solubility ofgreater than 100 mg/ml of water; the term “moderately soluble” includesdrugs with a solubility of between 100 mg/ml and 1 mg/ml of water; theterm “sparingly soluble” includes drugs with a solubility of between 1mg/ml and 0.1 mg/ml of water; and the term “insoluble” includes drugswith a solubility of less than 0.1 mg/ml of water.

The term “osmosis” refers to a spontaneous movement of a solvent from asolution of lower solute concentration to a solute or a solution ofhigher solute concentration through a semipermeable membrane, whereinthe membrane is permeable to the solvent and impermeable to the solute.

The term “osmotic pressure” refers to a pressure exerted on a highersolvent concentration side of the dosage form to inhibit solvent flowinto the dosage form.

The term “substantially free”, as used herein, refers to excluding anyfunctional (e.g., noncontaminating) amount, i.e., any amount thatcontributes or has an effect on release profile or lag time of thecomposition.

The term “semipermeable membrane”, as used herein, refers to a membraneor film that is substantially impermeable to the passage of solutes,e.g., a drug and other excipients, and substantially permeable topassage of fluids. As used herein, the terms functional coat andsemipermeable membrane are used interchangeably.

The term “coating weight gain”, as used herein, refers to coating weightgain with respect to the weight of the uncoated tablet. For example, acoating weight gain of 15% refers to a 15 wt % increase in tablet weightduring coating with respect to the uncoated tablet weight.

The terms “pore former” and the like, as used herein, refer towater-soluble polymers and/or water-soluble small molecules that willform pores or channels (i.e., behave as a channeling agent) in asemipermeable membrane to improve permeability of the membrane.

The terms “shear” and “shear effect,” as used interchangeably herein,refer to peristaltic waves, particularly under fed conditions, movingfrom the mid-corpus of the stomach to the pylorus. Dissolution ofcompositions using USP Apparatus II (Sinkers) at 50 rpm and 37° C. andusing USP Apparatus III (Biodis) at 25 dpm and 37° C., mimics theeffects of stomach shear on the dissolution rate of the composition.

The terms “orifice,” “hole”, and “delivery port,” as usedinterchangeably herein, refer to an opening/exit means in coatings,e.g., in the semipermeable membrane coat, the seal coat, and/or theovercoat, of an osmotic-controlled composition facing the placebo layer.The appropriate opening can be formed by any means, e.g., by manual orlaser drilling of the membrane. In certain embodiments, thesemipermeable membrane facing the top of the placebo layer is completelyremoved to provide an orifice comprising an optimum diameter that isequivalent to the diameter of the top of the placebo layer end of themultilayer core. In certain embodiments, the optimum orifice diameter isfrom about 0.6 mm and about 1.5 mm.

The term “osmotic agent” as used herein, refers to swellable hydrophilicpolymers, and osmogens/ionic compounds consisting of inorganic salts.

The term “wicking agent” as used herein, refers to a material with theability to draw water into the porous network of the osmoticcomposition. The wicking agent helps to increase the contact surfacearea of the drug with the incoming aqueous fluid.

The term “patient” or “subject,” as used herein, refers to a human ornonhuman mammal that is in need or may be in need to receive an osmoticdosage form of the present disclosure.

The terms “drug,” “active agent,” “active ingredient,” and “activepharmaceutical ingredient/agent” are used interchangeably herein andinclude compounds that will elicit a therapeutically useful response ina subject; such terms include all polymorphs, prodrugs, solvates,hydrates, pharmaceutically acceptable salts, esters, and functionallyequivalent chemical compounds.

The terms “methylphenidate” and “methylphenidate hydrochloride” are usedinterchangeably herein. The term “methylphenidate” includes allpharmaceutically acceptable salts, polymorphs, solvates, hydrates,esters, and functionally equivalent chemical compounds.

The terms “clonidine” and “clonidine hydrochloride” are usedinterchangeably herein. The term “clonidine” includes allpharmaceutically acceptable salts, esters, and functionally equivalentchemical compounds.

6.2 Multi-layer Osmotic Tablet Core

The present disclosure provides programmable osmotic-controlled oralcompositions comprising a multilayer core (e.g., a multilayer tabletcore) comprising a drug, wherein the core is coated with a semipermeablemembrane comprising an orifice and, optionally, an immediate releasecoating comprising a drug for immediate release, over the semipermeablemembrane. The multilayered tablet core comprises a pull layer containingthe drug and a push layer. The pull layer comprises at least two layers:a placebo layer, for providing a desired lag time for drug release; andan active layer containing the drug and providing a delayed controlledrelease of the drug. In certain embodiments, the orifice is present onthe placebo layer side of the multilayer tablet core. In certainembodiments, the delayed controlled release is a delayed extendedrelease. In certain embodiments, the tablets are vertically compressedproducing a capsule-shaped product. In certain embodiments, such shapeensures complete extrusion of drug from the orifice.

For any of the dosage forms, compositions, and methods of thedisclosure, the push layer is present in an amount that expands involume to a size that pushes the entire drug solution or suspension inthe pull layer, e.g., the placebo and active layers, out of the tabletthrough a delivery port/orifice, providing, e.g., complete drug recoveryfrom the dosage form. In certain embodiments, the pull layer and thepush layer are present in a ratio of about 2:1, about 1.5:1, about 1:1,or any intermediate values therein. In certain embodiments, the weightof the placebo layer, the active layer, or the push layer is from about10 wt % to about 60 wt %, based on the total weight of the trilayercore. In certain embodiments, the weight of the placebo layer is fromabout 10 wt % to about 50 wt %, based on the total weight of thetrilayer core. In certain embodiments, the weight of the active layer isfrom about 10 wt % to about 60 wt %, based on the total weight of thetrilayer core. In certain embodiments, the weight of the push layer isfrom about 10 wt % to about 50 wt %, based on the total weight of thetrilayer core. Furthermore, each of the layers, i.e., the active layer,the placebo layer, and the push layer, can comprise polyethylene oxide(e.g., POLYOX®).

In certain embodiments, the placebo layer and the push layer are free ofany active pharmaceutical ingredient. In certain embodiments, the activepharmaceutical ingredient contained in the active layer does notleach/migrate into the placebo layer or the push layer during the invitro drug release test. In certain embodiments, less that about 20 wt%, less than about 15 wt %, less than about 10 wt %, less than about 5wt %, or less than about 1 wt % of the total weight of the activepharmaceutical ingredient is released along with the placebo layer. Incertain embodiments, less that about 20 wt %, less than about 15 wt %,less than about 10 wt %, less than about 5 wt %, less than about 4 wt %,less than about 3 wt %, less than about 2 wt %, or less than about 1 wt% of the active pharmaceutical ingredient, based on the total weight ofthe active pharmaceutical agent in the dosage form, is released betweenabout 2 hours and about 10 hours, between about 2 hours and about 8hours, between about 2 hours and about 7 hours, or between about 2 hoursand about 6 hours following administration of the dosage form, therebyproviding a lag time.

Placebo Layer

In certain embodiments, the placebo layer/placebo layer blend, islocated adjacent to and continuity with the orifice in the semipermeablemembrane. In certain embodiments, the placebo layer blend comprises aswellable hydrophilic polymer, e.g., POLYOX® with an average molecularweight of from about 300,000 Da to about 900,000 Da, a binder, alubricant, and a glidant. In certain embodiments, the placebo layerfurther comprises a color pigment. In certain embodiments, the placebolayer blend is substantially free of any active pharmaceuticalingredient. In certain embodiments, the placebo layer contains less thanabout 30 wt %, less than about 25 wt %, less than about 20 wt %, lessthan about 15 wt %, less than about 10 wt %, less than about 5 wt %,less than 4 wt %, less than 3 wt %, less than 2 wt %, less than 1 wt %,or any intermediate values therein, of the active pharmaceuticalingredient, based on the total weight of the core.

In certain embodiments, the placebo layer blend further includes astabilizer to prevent degradation of polyethylene oxide polymer, e.g.,POLYOX®. In certain embodiments, the placebo layer blend furtherincludes at least one osmogen and/or at least one wicking agent. Incertain embodiments, placebo layer blend includes granules andextragranular excipients. In certain embodiments, the granules comprisea swellable hydrophilic polymer, a binder, an osmogen, a stabilizer, anda color pigment. In certain embodiments, granules further include awicking agent. In certain embodiments, glidant and lubricant are presentas extragranular excipients in the placebo layer. In certainembodiments, the granulating solvent for making granules comprisesalcoholic solvent comprising dehydrated alcohol. In certain embodiments,the granulation solvent comprises a hydroalcoholic solvent comprisingdehydrated alcohol and deionized water in varying ratios. In certainembodiments, the granulation solvent is a hydroalcoholic solventcontaining dehydrated alcohol:water ratio of between about 60:40 andabout 99:1. In certain embodiments, the placebo layer blend is made bydry granulation/slugging. In certain embodiments, the placebo layer ismade by direct compaction

In certain embodiments, the molecular weight/grade of the POLYOX® in theplacebo layer affects drug recovery, lag time, and/or release profile,of the composition. In certain embodiments, the POLYOX® has an averagemolecular weight of <about 1M, e.g., about 100K (POLYOX® N-10), about200K (POLYOX® N-80), about 300K (POLYOX®N-750), about 600K(POLYOX®N-205), about 900K (POLYOX®N-1105), or intermediate valuesthereof.

In certain embodiments, the viscosity of the placebo layer can beadjusted to provide a desired and consistent lag time. In certainembodiments, the viscosity of the placebo layer depends upon the averagemolecular weight of the POLYOX® present in the placebo layer. In certainembodiments, the placebo layer contains POLYOX® 205 or POLYOX® 1105. Incertain embodiments, the placebo layer contains POLYOX® 1105. In certainembodiments, the placebo layer contains POLYOX® 205. In certainembodiments, the POLYOX® is present in an amount of from about 50 wt %to about 99 wt %, from about 50 wt % to about 95 wt %, from about 50 wt% to about 90 wt %, from about 50 wt % to about 85 wt %, from about 50wt % to about 80 wt %, from about 50 wt % to about 75 wt %, from about50 wt % to about 70 wt %, from about 50 wt % to about 65 wt %, fromabout 50 wt % to about 60 wt %, from about 55 wt %, to about 99 wt %,from about 60 wt % to about 99 wt %, from about 65 wt % to about 99 wt%, from about 70 wt % to about 99 wt %, from about 75 wt % to about 99wt %, from about 80 wt % to about 99 wt %, from about 85 wt % to about99 wt %, from about 90 wt % to about 99 wt %, from about 95 wt % toabout 99 wt %, from about 55 wt % to about 95 wt %, from about 60 wt %to about 85 wt %, from about 65 wt % to about 80 wt %, or from about 70wt % to about 75 wt %, based on the total weight of the placebo layer.In certain embodiments, the POLYOX® is present in an amount of about 50wt %, about 55 wt %, about 60 wt %, about 65 wt %, about 70 wt %, about75 wt %, about 80 wt %, about 81 wt %, about 82 wt %, about 83 wt %,about 84 wt %, about 85 wt %, about 86 wt %, about 87 wt %, about 88 wt%, about 89 wt %, about 90 wt %, about 91 wt %, about 92 wt %, about 93wt %, about 94 wt %, about 95 wt %, about 96 wt %, about 97 wt %, about98 wt %, about 99 wt %, or any intermediate values therein, based on thetotal weight of the placebo layer.

In certain embodiments, the placebo layer comprises binders comprising,but not limited to, povidone (e.g., medium molecular weight KOLLIDON® 30LP), hypromellose, starch, acacia, gellan gum, low viscosityhydroxypropyl cellulose, methylcellulose, sodium methylcellulose,polyvinyl alcohol, polyvinyl acetates (e.g., KOLLICOAT® SR),polyethylene oxide (e.g., POLYOX®), polyethylene glycol, alginates,pegylated polyvinyl alcohol, or any combination thereof. In certainembodiments, the binder is povidone. In certain embodiments, the bindersare present in an amount of about 0.5 wt % to about 50 wt % of theplacebo layer. In certain embodiments, the binders are present in anamount of about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt%, about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt%, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19wt %, about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about24 wt %, about 25 wt %, about 25 wt %, about 26 wt %, about 27 wt %,about 28 wt %, about 29 wt %, about 30 wt %, about 31 wt %, about 32 wt%, about 33 wt %, about 34 wt %, about 35 wt %, about 36 wt %, about 37wt %, about 38 wt %, about 39 wt %, about 40 wt %, about 41 wt %, about42 wt %, about 43 wt %, about 44 wt %, about 45 wt %, about 46 wt %,about 47 wt %, about 48 wt %, about 49 wt %, about 50 wt %, or anyintermediates values therein, based on the total weight of the placebolayer.

In certain embodiments, the placebo layer includes at least onestabilizer to prevent/slow the degradation of POLYOX®. In certainembodiments, the stabilizer comprises antioxidants including ascorbicacid and its salts, tocopherols, sulfite salts such as sodiummetabisulfite or sodium sulfite, sodium sulfide, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbylpalmitate, propyl gallate, or any combination thereof. In certainembodiments, the antioxidant is BHT. In certain embodiments, thestabilizer is present in an amount of about 0.01 wt % to about 0.5 wt %of the placebo layer. In certain embodiments, the stabilizer is presentin an amount of about 0.01 wt %, about 0.02 wt %, about 0.03 wt %, about0.04 wt %, about 0.05 wt %, about 0.06 wt %, about 0.07 wt %, about 0.08wt %, about 0.09 wt %, about 0.10 wt %, about 0.2 wt %, about 0.3 wt %,about 0.4 wt %, about 0.5 wt %, or any intermediate values therein,based on the total weight of the placebo layer.

In certain embodiments, the placebo layer comprises at least onelubricant including magnesium stearate, glyceryl monostearates, palmiticacid, talc, carnauba wax, calcium stearate sodium, sodium or magnesiumlauryl sulfate, calcium soaps, zinc stearate, polyoxyethylenemonostearates, calcium silicate, silicon dioxide, hydrogenated vegetableoils and fats, stearic acid, and any combination thereof. In certainembodiments, the lubricant is magnesium stearate or steric acid. Incertain embodiments, the placebo layer comprises at least one lubricantas an extragranular excipient. In certain embodiments, the lubricant ispresent in an amount of about 0.5 wt % to about 2 wt %, based on thetotal weight of the placebo layer. In certain embodiments, the lubricantis present in an amount of about 0.5 wt %, about 0.6 wt %, about 0.7 wt%, about 0.8 wt %, about 0.9 wt %, about 1.0 wt %, about 1.1 wt %, about1.2 wt %, about 1.3 wt %, about 1.4 wt %, about 1.5 wt %, about 1.6 wt%, about 1.7 wt %, about 1.8 wt %, about 1.9 wt %, about 2.0 wt %, orany intermediate values therein, based on the total weight of theplacebo layer.

In certain embodiments, the placebo layer comprises at least oneglidant, including talc, colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, tribasic calcium phosphate, orany combinations thereof. In certain embodiments, the glidant iscolloidal silicon dioxide. In certain embodiments, the placebo layercomprises at least one glidant as an extragranular excipient. In certainembodiments, the glidant is present in an amount of from about 0.05 wt %to about 5 wt %, from about 0.1 wt % to about 5 wt %, from about 0.5 wt% to about 5 wt %, from about 1 wt % to about 5 wt %, from about 1.5 wt% to about 5 wt %, from about 2 wt % to about 5 wt %, from about 2.5 wt% to about 5 wt %, from about 3 wt % to about 5 wt %, from about 3.5 wt% to about 5 wt %, from about 4 wt % to about 5 wt %, from about 4.5 wt% to about 5 wt %, from about 0.05 wt % to about 4.5 wt %, from about0.05 wt % to about 4.0 wt %, from about 0.05 wt % to about 3.5 wt %,from about 0.05 wt % to about 3.0 wt %, from about 0.05 wt % to about2.5 wt %, from about 0.05 wt % to about 2.0 wt %, from about 0.05 wt %to about 1.5 wt %, from about 0.05 wt % to about 1.0 wt %, from about0.05 wt % to about 0.5 wt %, from about 0.05 wt % to about 0.1 wt %,from about 0.1 wt % to about 4.5 wt %, from about 1 wt % to about 4 wt%, or from about 1.5 wt % to about 3 wt %, based on the total weight ofthe placebo layer. In certain embodiments, the glidant is present in anamount of about 0.05 wt %, about 0.1 wt %, about 0.2 wt %, about 0.3 wt%, about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about0.8 wt %, about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %,about 4 wt %, about 5 wt %, or any intermediate valued therein, based onthe total weight of the placebo layer.

In certain embodiments, the placebo layer includes at least one colorpigment. In certain embodiments, the color pigment in the placebo layeris useful for distinguishing the placebo layer from the active layer. Incertain embodiments, the color pigment comprises iron oxide orlake-based colors. In certain embodiments, the pigment is a lake-basedcolor. In certain embodiments, the pigment is an iron oxide pigment,e.g., oxide pigment red or oxide pigment black. In certain embodiments,the pigment is present in an amount of about 0.01 wt % to about 0.5 wt%, based on the total weight of the placebo layer.

In certain embodiments, the placebo layer further comprises osmogens,any disintegrants or water-entraining agents/wicking agents.

In certain embodiments, the osmogen is an ionic compound comprising, butnot limited to, sodium chloride, potassium chloride, potassium sulfate,lithium sulfate, sodium sulfate, lactose-sucrose, lactose-dextrose,mannitol-dextrose, mannitol-lactose, lactose-fructose,dextrose-fructose, sucrose, dextrose, mannitol, sorbitol, xylitol,dibasic sodium phosphate, and combinations thereof. In certainembodiments, the osmogen is sodium chloride. In certain embodiments, theosmogen is present in an amount of from about 5 wt % to about 40 wt %,based on the total weight of the placebo layer. In certain embodiments,the osmogen is present in an amount of about 5 wt %, about 6 wt %, about7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about12 wt %, about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %,about 17 wt %, about 18 wt %, about 19 wt %, about 20 wt %, about 21 wt%, about 22 wt %, about 23 wt %, about 24 wt %, about 25 wt %, about 26wt %, about 27 wt %, about 28 wt %, about 29 wt %, about 30 wt %, about31 wt %, about 32 wt %, about 33 wt %, about 34 wt %, about 35 wt %,about 36 wt %, about 37 wt %, about 38 wt %, about 39 wt %, about 40 wt%, or any intermediate values therein, based on the total weight of theplacebo layer.

In certain embodiments, the placebo layer comprises at least one wickingagent selected from the group comprising crospovidone, croscarmellosesodium, carmellose calcium, polyvinyl pyrolidone, low-substitutedhydroxypropyl celluloses, sodium starch glycolate, alginic acid andalginates, acrylic acid derivatives, corn starch, maize starch, modifiedstarches, and combinations thereof. In certain embodiments, the wickingagent is crospovidone. In certain embodiments, the wicking agent ispresent in an amount of from about 5 wt % to about 40 wt %, based on thetotal weight of the placebo layer. In certain embodiments, the wickingagent is present in an amount of 5 wt %, about 6 wt %, about 7 wt %,about 8 wt %, about 9 wt %, about 10 wt %, about 11 wt %, about 12 wt %,about 13 wt %, about 14 wt %, about 15 wt %, about 16 wt %, about 17 wt%, about 18 wt %, about 19 wt %, about 20 wt %, about 21 wt %, about 22wt %, about 23 wt %, about 24 wt %, about 25 wt %, about 26 wt %, about27 wt %, about 28 wt %, about 29 wt %, about 30 wt %, about 31 wt %,about 32 wt %, about 33 wt %, about 34 wt %, about 35 wt %, about 36 wt%, about 37 wt %, about 38 wt %, about 39 wt %, about 40 wt %, or anyintermediate values therein, based on the total weight of the placebolayer.

In certain embodiments, the relative weight percentage of the placebolayer, based on the total weight of the uncoated trilayer core, can bebetween about 10 wt % and about 60 wt %, between about 10 wt % and about55 wt %, or between about 10 wt % and about 50 wt %.

Active Layer

In certain embodiments, the active layer is located between (andadjacent to) and in contact with the placebo layer and the push layer.In certain embodiments, the active layer/active layer blend includes anactive agent, a swellable hydrophilic polymer, a binder, an osmogen, anda lubricant. In certain embodiments, the active layer/active layer blendfurther includes a glidant and/or a stabilizer. In certain embodiments,active layer blend includes granules containing an active agent, aswellable hydrophilic polymer, a binder, an osmogen, a stabilizer, and acolor pigment. In certain embodiments, granules further include asurfactant and/or a wicking agent. In certain embodiments, the glidantsand the lubricants are present as extragranular excipients in the activelayer blend.

In certain embodiments, the granulating solvent for making granulescomprises alcoholic solvent comprising dehydrated alcohol. In certainembodiments, the granulation solvent comprises a hydroalcoholic solventcomprising dehydrated alcohol and deionized water in varying weightratios. In certain embodiments, the granulation solvent is ahydroalcoholic solvent containing dehydrated alcohol:water weight ratioof between about 60:40 and about 99:1. In certain embodiments, theplacebo layer blend is made by dry granulation/slugging. In certainembodiments, the placebo layer is made by direct compaction In certainembodiments, the swellable hydrophilic polymers include polyethyleneoxide, carbopols, polyacrylamides, acrylate polymer polysaccharidecomposed of condensed glucose units, crospovidone, carboxymethylcellulose, and poly(alkalicarboxymethylcellulose), Methocel™ K100LVCR(methylcellulose and hydroxypropyl methyl cellulose), and anycombinations thereof. In certain embodiments, the swellable hydrophilicpolymers comprise polyethylene oxide polymers with an average molecularweight of from about 100,000 Da to about 600,000 Da. In certainembodiments, the polyethylene oxide polymer has an average molecularweight of about 100,000 Da (POLYOX® N-10), about 200,000 Da (POLYOX®N-80), about 300,000 Da (POLYOX®N-750), or about 600.00 Da. In certainembodiments, the average molecular weight of POLYOX® is about 200,000Da.

In certain embodiments, the viscosity of the active layer is adjusted toprovide a desired and consistent release profile. In certainembodiments, the viscosity of active layer depends upon the averagemolecular weight/grade of the POLYOX® present in the active layer. Incertain embodiments, the active layer contains POLYOX®N-80 (200K). Incertain embodiments, the POLYOX® is present in an amount of from about30 wt % to about 80 wt %, from about 35 wt % to about 80 wt %, fromabout 40 wt % to about 80 wt %, from about 45 wt %, to about 80 wt %,from about 50 wt % to about 80 wt %, from about 55 wt % to about 80 wt%, from about 60 wt % to about 80 wt %, from about 65 wt % to about 80wt %, from about 70 wt % to about 80 wt %, from about 75 wt % to about80 wt %, from about 50 wt % to about 75 wt %, from about 50 wt % toabout 70 wt %, from about 50 wt % to about 65 wt %, from about 50 wt %to about 60 wt %, from about 50 wt % to about 55 wt %, from about 55 wt% to about 75 wt %, or from about 60 wt % to about 70 wt % of the activelayer. In certain embodiments, the POLYOX® is present in an amount ofabout 40 wt %, about 45 wt %, about 50 wt %, about 55 wt %, about 60 wt%, about 65 wt %, about 70 wt %, about 75 wt %, about 80 wt %, orintermediate values therein, based on the total weight of the activelayer.

In certain embodiments, drug to POLYOX® weight ratio, in the activelayer, affects the lag time, release rate, and drug recovery of thecomposition. In certain embodiments, release rate and drug recovery fromthe composition increases with increasing the drug to POLYOX® weightratio. In certain embodiments, lag time decreases with increasing drugto POLYOX® weight ratio. In certain embodiments, the ratio of the drugand POLYOX® is between about 10:90 and about 90:10. In certainembodiments, the weight ratio of the drug and POLYOX® is about 10:90,about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about70:30, about 80:20, about 90:10, or intermediate values therein. Incertain embodiments, the drug:POLYOX® weight ratio is from about 20:80and about 70:30.

In certain embodiments, the active layer further includes low viscosityhypromellose or hypromellose acetate succinate as a wicking agent toenhance wettability of drugs with low aqueous solubility. In certainembodiments, the low viscosity hypromellose or povidone are used asbinders, and stearic acid is used as a lubricant.

In certain embodiments, the active layer comprises binders includingpovidone (e.g., medium molecular weight KOLLIDON® 30 LP), hypromellose,starch, acacia, gellan gum, low viscosity hydroxypropyl cellulose,methylcellulose, sodium methylcellulose, polyvinyl alcohol, polyvinylacetates (e.g., KOLLICOAT® SR), polyethylene oxide, polyethylene glycol,alginates, pegylated polyvinyl alcohol, or any combination thereof. Incertain embodiments, the binder is povidone. In certain embodiments, thebinders are present in an amount of about 0.5 wt % to about 30 wt %, 0.5wt % to about 29 wt %, from about 0.5 wt % to about 28 wt %, from about0.5 wt % to about 27 wt %, from about 0.5 wt % to about 26 wt %, fromabout 0.5 wt % to about 25 wt %, from about 0.5 wt % to about 24 wt %,from about 0.5 wt % to about 23 wt %, from about 0.5 wt % to about 22 wt%, from about 0.5 wt % to about 21 wt %, from about 0.5 wt % to about 20wt %, from about 0.5 wt % to about 19 wt %, from about 0.5 wt % to about18 wt %, from about 0.5 wt % to about 17 wt %, from about 0.5 wt % toabout 16 wt %, from about 0.5 wt % to about 15 wt %, from about 0.5 wt %to about 14 wt %, from about 0.5 wt % to about 13 wt %, from about 0.5wt % to about 12 wt %, from about 0.5 wt % to about 11 wt %, from about0.5 wt % to about 10 wt %, from about 0.5 wt % to about 9 wt %, fromabout 0.5 wt % to about 8 wt %, from about 0.5 wt % to about 7 wt %,from about 0.5 wt % to about 6 wt %, from about 0.5 wt % to about 5 wt%, from about 0.5 wt % to about 4 wt %, from about 0.5 wt % to about 3wt %, from about 0.5 wt % to about 2 wt %, from about 0.5 wt % to about1 wt %, from about 1 wt % to about 20 wt %, from about 2 wt %, to about20 wt %, from about 3 wt % to about 20 wt %, from about 4 wt % to about20 wt %, from about 5 wt % to about 20 wt %, from about 6 wt % to about20 wt %, from about 7 wt % to about 20 wt %, from about 8 wt % to about20 wt %, from about 9 wt % to about 20 wt %, from about 10 wt % to about20 wt %, from about 11 wt % to about 20 wt %, from about 12 wt % toabout 20 wt %, from about 13 wt % to about 20 wt %, from about 14 wt %to about 20 wt %, from about 15 wt % to about 20 wt %, from about 16 wt% to about 20 wt %, from about 17 wt % to about 20 wt %, from about 18wt % to about 20 wt %, from about 19 wt % to about 20 wt %, from about 5wt % to about 15 wt %, from about 5 wt % to about 10 wt %, or from about10 wt % to about 15 wt %, based on the total weight of the active layer.

In certain embodiments, the active layer comprises osmogens and/or anydisintegrants or water-entraining agents/wicking agents. In certainembodiments, the active layer comprises at least one osmogen. In certainembodiments, the osmogen includes ionic compounds of inorganic saltsthat provide a concentration differential for osmotic flow of liquidinto the composition. In certain embodiments, the osmogen comprises anionic compound including sodium chloride, potassium chloride, potassiumsulfate, lithium sulfate, sodium sulfate, a lactose and sucrosecombination, a lactose and dextrose combination, sucrose, dextrose,mannitol, dibasic sodium phosphate, and any combination thereof. Incertain embodiments, the osmogen is sodium chloride. In certainembodiments, the osmogen is present in an amount of from about 2 wt % toabout 40 wt %, from about 2 wt % to about 35 wt %, from about 2 wt % toabout 30 wt %, from about 2 wt % to about 25 wt %, from about 2 wt % toabout 20 wt %, from about 2 wt % to about 19 wt %, from about 2 wt % toabout 18 wt %, from about 2 wt % to about 17 wt %, from about 2 wt % toabout 16 wt %, from about 2 wt % to about 15 wt %, from about 2 wt % toabout 14 wt %, from about 2 wt % to about 13 wt %, from about 2 wt % toabout 12 wt %, from about 2 wt % to about 11 wt %, from about 2 wt % toabout 10 wt %, from about 2 wt % to about 9 wt %, from about 2 wt % toabout 8 wt %, from about 2 wt % to about 7 wt %, from about 2 wt % toabout 6 wt %, from about 2 wt % to about 5 wt %, from about 2 wt % toabout 4 wt %, from about 2 wt % to about 3 wt %, from about 3 wt % toabout 20 wt %, from about 4 wt % to about 20 wt %, from about 5 wt % toabout 20 wt %, from about 6 wt % to about 20 wt %, from about 7 wt % toabout 20 wt %, from about 8 wt % to about 20 wt %, from about 9 wt % toabout 20 wt %, from about 10 wt % to about 20 wt %, from about 11 wt %to about 20 wt %, from about 12 wt % to about 20 wt %, from about 13 wt% to about 20 wt %, from about 14 wt % to about 20 wt %, from about 15wt % to about 20 wt %, from about 16 wt % to about 20 wt %, from about17 wt % to about 20 wt %, from about 18 wt % to about 20 wt %, fromabout 19 wt % to about 20 wt %, from about 5 wt % to about 15 wt %, fromabout 5 wt % to about 10 wt %, or from about 10 wt % to about 15 wt %,based on the total weight of the active layer. In certain embodiments,the osmogen is present in an amount of about 2 wt %, about 3 wt %, about4 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9wt %, about 10 wt %, about 15 wt %, about 20 wt %, about 21 wt %, about22 wt %, about 23 wt %, about 24 wt %, about 25 wt %, about 26 wt %,about 27 wt %, about 28 wt %, about 29 wt %, about 30 wt %, about 31 wt%, about 32 wt %, about 33 wt %, about 34 wt %, about 35 wt %, about 36wt %, about 37 wt %, about 38 wt %, about 39 wt %, about 40 wt %, or anyintermediate values therein, based on the total weight of the activelayer.

In certain embodiments, the active layer comprises at least one wickingagent selected from the group comprising crospovidone, croscarmellosesodium, carmellose calcium, polyvinyl pyrolidone, low-substitutedhydroxypropyl celluloses, sodium starch glycolate, alginic acid andalginates, acrylic acid derivatives, corn starch, maize starch, modifiedstarches, and combinations thereof. In certain embodiments, the wickingagent is crospovidone. In certain embodiments, the wicking agent ispresent in an amount of from about 5 wt % to about 40 wt %, from about 5wt % to about 35 wt %, from about 5 wt % to about 30 wt %, from about 5wt % to about 25 wt %, from about 5 wt % to about 20 wt %, from about 5wt % to about 15 wt %, from about 5 wt % to about 10 wt %, from about 10wt % to about 20 wt %, from about 15 wt % to about 20 wt %, or fromabout 10 wt % to about 15 wt %, based on the total weight of the activelayer. In certain embodiments, the wicking agent is present in an amountof about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt%, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19wt %, about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about24 wt %, about 25 wt %, about 26 wt %, about 27 wt %, about 28 wt %,about 29 wt %, about 30 wt %, about 31 wt %, about 32 wt %, about 33 wt%, about 34 wt %, about 35 wt %, about 36 wt %, about 37 wt %, about 38wt %, about 39 wt %, about 40 wt %, or any intermediate values therein,based on the total weight of the active layer.

In certain embodiments, the active layer includes at least onestabilizer to prevent/reduce the degradation of POLYOX®. In certainembodiments, the stabilizer comprises an antioxidant and/or a pHmodifying agent. In certain embodiments, the pH modifying agent is anacid or a base. In certain embodiments, the stabilizer is an antioxidantand a pH modifying agent. In certain embodiments, the stabilizercomprises an antioxidant including one or more of ascorbic acid and itssalts, tocopherols, sulfite salts such as sodium metabisulfite or sodiumsulfite, sodium sulfide, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), ascorbyl palmitate, and propyl gallate. In certainembodiments, the antioxidant is BHT. In certain embodiments, additionalstabilizers, e.g., pH modifiers, can be added to stabilize the activeagent. In certain embodiments, the stabilizer is present in an amount ofabout 0.01 wt % to about 0.5 wt %, from about 0.1 wt % to about 0.5 wt%, from about 0.2 wt % to about 0.5 wt %, from about 0.3 wt % to about0.5 wt %, from about 0.4 wt % to about 0.5 wt %, from about 0.01 wt % toabout 0.5 wt %, from about 0.01 wt % to about 0.4 wt %, from about 0.01wt % to about 0.3 wt %, from about 0.01 wt % to about 0.2 wt %, fromabout 0.01 wt % to about 0.1 wt %, or from about 0.05% to about 0.3 wt%, based on the total weight of the active layer. In certainembodiments, the stabilizer is present in an amount of about 0.01 wt %,about 0.02 wt %, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %,about 0.06 wt %, about 0.07 wt %, about 0.08 wt %, about 0.09 wt %,about 0.1 wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about0.5 wt %, or any intermediate values therein, based on the total weightof the active layer.

In certain embodiments, the active layer further includes surfactants tomodulate the solubility of the active agent. In certain embodiments, thesurfactant comprises one or more of esters of fatty acids; sorbitanfatty acid esters ethoxylated with from about 2 to about 30 moles ofethylene oxide; polyethylene glycol fatty acid esters; polyethyleneglycol esters and polyethylene glycol ethers; and polyethoxylatedcarboxylic acids, PEG-7 hydrogenated castor oil, and PEG-30dipolyhydroxystearate; block copolymers based on ethylene oxide andpropylene oxide; dioctyl sodium sulfosuccinate (docusate sodium); sodiumlauryl sulfate; PEG-32 glyceryl laurate; PEG-32 glycerylpalmitostearate; PEG-8 glyceryl caprylate/caprate; PEG-6 glycerylcaprylate/caprate; macrogol 15 hydroxystearate; polyoxyethylene 20sorbitan monolaurate (polysorbate 20); polyoxyethylene 20 sorbitanmonooleate (polysorbate 80); sorbitan monolaurate; sorbitan monooleate;and polyoxyl 40 stearate.

In certain embodiments, the active layer comprises lubricants includingmagnesium stearate, glyceryl monostearates, palmitic acid, talc,carnauba wax, calcium stearate sodium, sodium or magnesium laurylsulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates,calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats,stearic acid, or any combination thereof. In certain embodiments, thelubricant is present in an amount of about 0.01 wt % to about 2 wt %,from about 0.01 wt % to about 1.5 wt %, from about 0.01 wt % to about1.0 wt %, from about 0.01 wt % to about 0.5 wt %, from about 0.01 wt %to about 0.1 wt %, from about 0.1 wt % to about 2 wt %, from about 1.0wt % to about 2.0 wt %, from about 1.5 wt % to about 2.0 wt %, fromabout 0.1 wt % to about 1.0 wt %, or from about 0.5 wt % to about 1.5 wt% based on the total weight of the active layer. In certain embodiments,the lubricant is present in an amount of about 0.01 wt %, about 0.02 wt%, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %, about 0.1 wt %,about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about 1.0 wt%, about 1.1 wt %, about 1.2 wt %, about 1.3 wt %, about 1.4 wt %, about1.5 wt %, about 1.6 wt %, about 1.7 wt %, about 1.8 wt %, about 1.9 wt%, about 2.0 wt %, or any intermediate values therein, based on thetotal weight of the active layer.

In certain embodiments, the active layer comprises glidants includingtalc, colloidal silicon dioxide, magnesium trisilicate, powderedcellulose, starch, tribasic calcium phosphate, or a mixture thereof. Incertain embodiments, the glidant is colloidal silicon dioxide. Incertain embodiments, the glidant is present in an amount of about 0.05wt % to about 5 wt %, from about 0.05 wt % to about 4 wt %, from about0.05 wt % to about 3 wt %, from about 0.05 wt % to about 2 wt %, fromabout 0.05 wt % to about 1.0 wt %, from about 0.05 wt % to about 0.5 wt%, from about 0.1 wt % to about 5 wt %, from about 1.0 wt % to about 5wt %, from about 1.5 wt % to about 5 wt %, from about 2.0 wt % to about5 wt %, from about 2.5 wt % to about 5 wt %, from about 3.0 wt % toabout 5 wt %, from about 3.5 wt % to about 5 wt %, from about 4.0 wt %to about 5 wt %, from about 4.5 wt % to about 5 wt %, from about 0.1 wt% to about 4.5 wt %, from about 1 wt % to about 4 wt %, or from about1.5 wt % to about 3 wt %, based on the total weight of the active layer.In certain embodiments, the glidant is present in an amount of about 0.1wt %, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %,about 0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about 1wt %, about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, or anyintermediate valued therein, based on the total weight of the activelayer.

In certain embodiments, the relative weight percentage of the activelayer, based on the total weight of the uncoated trilayer core, can bebetween about 10 wt % and about 60 wt %, between about 15 wt % and about50 wt %, between about 20 wt % and about 45 wt %, between about 25 wt %and about 40 wt %, or about 30 wt %.

Push Layer

In certain embodiments, the push layer is located adjacent to the activelayer. In certain embodiments, the push layer/push layer blend includesa swellable hydrophilic polymer, a binder, an osmogen, a lubricant, anda color pigment. In certain embodiments, the push layer/push layer blendfurther includes a glidant and/or a stabilizer. In certain embodiments,the push layer blend includes granules containing a swellablehydrophilic polymer, a binder, an osmogen, a stabilizer, and a colorpigment. In certain embodiments, the glidants and the lubricants arepresent as extragranular excipients in the push layer blend. In certainembodiments, the granulating solvent for making granules comprisesalcoholic solvent comprising absolute alcohol. In certain embodiments,the granulation solvent comprises a hydroalcoholic solvent comprisingabsolute alcohol and deionized water in varying weight ratios. Incertain embodiments, the granulation solvent is a hydroalcoholic solventcontaining absolute alcohol:water weight ratio of between about 60:40and about 99:1. In certain embodiments, the push layer blend is made bydry granulation/slugging. In certain embodiments, the push layer is madeby direct compaction.

In certain embodiments, the push layer does not include any drug. Incertain embodiments, the swellable hydrophilic polymer is a polyethyleneoxide polymer having an average molecular weight of greater than orequal to 1000,000 Da.

In certain embodiments, the average molecular weight of the polyethyleneoxide polymer in the push layer is about 1000,000 Da (POLYOX® WSR N12K), about 2000,000 Da (POLYOX® WSR N 60K), about 4000,000 Da (POLYOX®WSR 301), about 5000,000 Da (POLYOX® WSR coagulant), about 7000,000 Da(POLYOX® WSR 303), or any intermediate values therein. In certainembodiments, swelling of POLYOX® WSR coagulant (5M) can be enhanced bymixing with a portion of POLYOX® WSR 303 (7M). In certain embodiments,swelling of POLYOX® coagulant can be reduced by mixing with a portion ofPOLYOX®WSR 301 (4M). In certain embodiments, the POLYOX® is present inan amount of about 40 wt % to about 80 wt %, from about 40 wt % to about75 wt %, from about 40 wt % to about 70 wt %, from about 40 wt % toabout 65 wt %, from about 40 wt % to 60 wt %, from about 40 wt % to 55wt %, from about 40 wt % to 50 wt %, from about 40 wt % to 45 wt %, fromabout 45 wt % to about 80 wt %, from about 50 wt % to about 80 wt %,from about 55 wt % to about 80 wt %, from about 60 wt % to about 80 wt%, from about 65 wt % to about 80 wt %, from about 70 wt % to about 80wt %, from about 75 wt % to about 80 wt %, from about 45 wt % to about75 wt %, from about 50 wt % to about 70 wt %, or from about 55 wt % toabout 65 wt %, based on the total weight of the push layer. In certainembodiments, the POLYOX® is present in an amount of about 45 wt %, about50 wt %, about 55 wt %, about 60 wt %, about 65 wt %, about 70 wt %,about 75 wt %, about 80 wt %, or any intermediate values therein, basedon the total weight of the push layer.

In certain embodiments, the amount and grade of the POLYOX® present inthe push layer affects the release profile of the drug from the dosageform, i.e., an increase in the molecular weight or amount of POLYOX® inthe push layer will increase the force exerted on the pull layer forfast and complete drug recovery. In certain embodiments, the grade ofPOLYOX® is selected to provide desired lag time, release rate, andcomplete drug recovery in about 22 hours from the time of administrationof the dosage form.

In certain embodiments, the push layer comprises at least one osmogen.In certain embodiments, the presence of osmogen in the push layer isessential for uniform swelling of the tablet core. In certainembodiments, the osmogen provides a concentration gradient for osmoticflow of liquid into the composition. The rate at which the polyethyleneoxide polymer in the push layer absorbs water depends on the osmoticpressure generated by the osmogen present in the push layer, and thepermeability of the semipermeable membrane/functional coat. As thepolyethylene oxide polymer present in the push layer absorbs water, itexpands in volume, which pushes the drug solution or suspension in thepull layer out of the tablet through the orifice/hole in the membrane.The compositions release drug at a rate, which is independent of pH andhydrodynamics of the dissolution medium.

In certain embodiments, the osmogen is an ionic compound comprising, butnot limited to, sodium chloride, potassium chloride, potassium sulfate,lithium sulfate, sodium sulfate, lactose-sucrose, lactose-dextrose,mannitol-dextrose, mannitol-lactose, lactose-fructose,dextrose-fructose, sucrose, dextrose, mannitol, sorbitol, xylitol,dibasic sodium phosphate, and combinations thereof. In certainembodiments, the osmogen is sodium chloride. In certain embodiments, theosmogen is present in an amount of about 5 wt % to about 40 wt %, fromabout 5 wt % to about 35 wt %, from about 5 wt % to about 30 wt %, fromabout 5 wt % to about 25 wt %, from about 5 wt % to about 20 wt %, fromabout 5 wt % to about 15 wt %, from about 5 wt % to about 10 wt %, fromabout 10 wt % to about 30 wt %, from about 15 wt % to about 30 wt %,from about 20 wt % to about 30 wt %, from about 25 wt % to about 30 wt%, or from about 10 wt % to about 25 wt %, or from about 15 wt % toabout 20 wt %, based on the total weight of the push layer. In certainembodiments, the osmogen is present in an amount of about 5 wt %, about6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, about 10 wt %, about11 wt %, about 12 wt %, about 13 wt %, about 14 wt %, about 15 wt %,about 16 wt %, about 17 wt %, about 18 wt %, about 19 wt %, about 20 wt%, about 21 wt %, about 22 wt %, about 23 wt %, about 24 wt %, about 25wt %, about 26 wt %, about 27 wt %, about 28 wt %, about 29 wt %, about30 wt %, about 31 wt %, about 32 wt %, about 33 wt %, about 34 wt %,about 35 wt %, about 36 wt %, about 37 wt %, about 38 wt %, about 39 wt%, about 40 wt %, or any intermediate values therein, based on the totalweight of the push layer. In certain embodiments, the osmogen is presentin an amount of from about 10 wt % to about 30 wt %, based on the totalweight of the push layer.

In certain embodiments, the push layer includes at least one binderselected from the group consisting of, but not limited toto, povidone(e.g., medium molecular weight KOLLIDON® 30 LP), hypromellose, starch,acacia, gellan gum, low viscosity hydroxypropyl cellulose,methylcellulose, sodium methylcellulose, polyvinyl alcohol, polyvinylacetates (e.g., KOLLICOAT® SR), polyethylene oxide, polyethylene glycol,alginates, pegylated polyvinyl alcohol, and any combination thereof. Incertain embodiments, the binder is povidone. In certain embodiments, thebinders are present in an amount of about 0.5 wt % to about 30 wt %,from about 0.5 wt % to about 29 wt %, from about 0.5 wt % to about 28 wt%, from about 0.5 wt % to about 27 wt %, from about 0.5 wt % to about 26wt %, from about 0.5 wt % to about 25 wt %, from about 0.5 wt % to about24 wt %, from about 0.5 wt % to about 23 wt %, from about 0.4 wt % toabout 22 wt %, from about 0.5 wt % to about 21 wt %, from about 0.5 wt %to about 20 wt %, from about 0.5 wt % to about 19 wt %, from about 0.5wt % to about 18 wt %, from about 0.5 wt % to about 17 wt %, from about0.5 wt % to about 16 wt %, from about 0.5 wt % to about 15 wt %, fromabout 0.5 wt % to about 14 wt %, from about 0.5 wt % to about 13 wt %,from about 0.5 wt % to about 12 wt %, from about 0.5 wt % to about 11 wt%, from about 0.5 wt % to about 10 wt %, from about 0.5 wt % to about 9wt %, from about 0.5 wt % to about 8 wt %, from about 0.5 wt % to about7 wt %, from about 0.5 wt % to about 6 wt %, from about 0.5 wt % toabout 5 wt %, from about 0.5 wt % to about 4 wt %, from about 0.5 wt %to about 3 wt %, from about 0.5 wt % to about 2 wt %, from about 0.5 wt% to about 1 wt %, from about 1 wt % to about 20 wt %, from about 2 wt%, to about 20 wt %, from about 3 wt % to about 20 wt %, from about 4 wt% to about 20 wt %, from about 5 wt % to about 20 wt %, from about 6 wt% to about 20 wt %, from about 7 wt % to about 20 wt %, from about 8 wt% to about 20 wt %, from about 9 wt % to about 20 wt %, from about 10 wt% to about 20 wt %, from about 11 wt % to about 20 wt %, from about 12wt % to about 20 wt %, from about 13 wt % to about 20 wt %, from about14 wt % to about 20 wt %, from about 15 wt % to about 20 wt %, fromabout 16 wt % to about 20 wt %, from about 17 wt % to about 20 wt %,from about 18 wt % to about 20 wt %, from about 19 wt % to about 20 wt%, from about 5 wt % to about 15 wt %, from about 5 wt % to about 10 wt%, or from about 10 wt % to about 15 wt %, based on the total weight ofthe push layer. In certain embodiments, the binders are present in anamount of about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about 0.8 wt%, about 0.9 wt %, about 1 wt %, about 2 wt %, about 3 wt %, about 4 wt%, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %,about 10 wt %, about 11 wt %, about 12 wt %, about 13 wt %, about 14 wt%, about 15 wt %, about 16 wt %, about 17 wt %, about 18 wt %, about 19wt %, about 20 wt %, about 21 wt %, about 22 wt %, about 23 wt %, about24 wt %, about 25 wt %, about 25 wt %, about 26 wt %, about 27 wt %,about 28 wt %, about 29 wt %, about 30 wt %, or any intermediates valuestherein, based on the total weight of the push layer.

In certain embodiments, the push layer includes at least one stabilizerto prevent/reduce degradation of POLYOX®. In certain embodiments, thestabilizer comprises, but is not limited to, ascorbic acid, tocopherols,sulfite salts such as sodium metabisulfite or sodium sulfite, sodiumsulfide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),ascorbyl palmitate, propyl gallate, or any combination thereof. Incertain embodiments, the stabilizer is BHT. In certain embodiments, thestabilizer is present in an amount of about 0.01 wt % to about 0.5 wt %,from about 0.1 wt % to about 0.5 wt %, from about 0.2 wt % to about 0.5wt %, from about 0.3 wt % to about 0.5 wt %, from about 0.4 wt % toabout 0.5 wt %, from about 0.01 wt % to about 0.4 wt %, from about 0.01wt % to about 0.3 wt %, from about 0.01 wt % to about 0.2 wt %, fromabout 0.01 wt % to about 0.1 wt %, or from about 0.05% to about 0.3 wt%, based on the total weight of the push layer. In certain embodiments,the stabilizer is present in an amount of about 0.01 wt %, about 0.02 wt%, about 0.03 wt %, about 0.04 wt %, about 0.05 wt %, about 0.06 wt %,about 0.07 wt %, about 0.08 wt %, about 0.09 wt %, about 0.1 wt %, about0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, or anyintermediate values therein, based on the total weight of the pushlayer.

In certain embodiments, the push layer includes lubricants comprising,but not limited to, magnesium stearate, glyceryl monostearates, palmiticacid, talc, carnauba wax, calcium stearate sodium, sodium or magnesiumlauryl sulfate, calcium soaps, zinc stearate, polyethylene oxide,polyethylene glycols, polyoxyethylene monostearates, calcium silicate,silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, orany combination thereof. In certain embodiments, the lubricant ispresent in an amount of about 0.1 wt % to about 2 wt %, from about 0.1wt % to about 1.5 wt %, from about 0.1 wt % to about 1.0 wt %, fromabout 0.1 wt % to about 0.5 wt %, from about 0.5 wt % to about 2 wt %,from about 1.0 wt % to about 2.0 wt %, from about 1.5 wt % to about 2.0wt %, or from about 1.0 wt % to about 1.5 wt %, based on the totalweight of the push layer. In certain embodiments, the lubricant ispresent in an amount of about 0.1 wt %, about 0.2 wt %, about 0.3 wt %,about 0.4 wt %, about 0.5 wt %, about 0.6 wt %, about 0.7 wt %, about0.8 wt %, about 0.9 wt %, about 1.0 wt %, about 1.1 wt %, about 1.2 wt%, about 1.3 wt %, about 1.4 wt %, about 1.5 wt %, about 1.6 wt %, about1.7 wt %, about 1.8 wt %, about 1.9 wt %, about 2.0 wt %, or anyintermediate values therein, based on the total weight of the pushlayer.

In certain embodiments, the push layer includes at least one glidantcomprising, but not limited to, talc, colloidal silicon dioxide,magnesium trisilicate, powdered cellulose, starch, and tribasic calciumphosphate. In certain embodiments, the glidant is colloidal silicondioxide. In certain embodiments, the glidant is present in an amount ofabout 0.05 wt % to about 5 wt %, from about 0.1 wt % to about 1.5 wt %,from about 0.1 wt % to about 1.0 wt %, from about 0.1 wt % to about 0.5wt %, from about 0.5 wt % to about 2 wt %, from about 1.0 wt % to about2.0 wt %, from about 1.5 wt % to about 2.0 wt %, or from about 1.0 wt %to about 1.5 wt %, based on the total weight of the push layer. Incertain embodiments, the glidant is present in an amount of about 0.1 wt%, about 0.2 wt %, about 0.3 wt %, about 0.4 wt %, about 0.5 wt %, about0.6 wt %, about 0.7 wt %, about 0.8 wt %, about 0.9 wt %, about 1 wt %,about 2 wt %, about 3 wt %, about 4 wt %, about 5 wt %, or anyintermediate valued therein, based on the total weight of the pushlayer.

In certain embodiments, the push layer includes at least one colorpigment for identifying the push layer in the multilayer tablet core. Incertain embodiments, the push layer and the placebo layer include thesame color pigment. In certain embodiments, the placebo layer containsless amount of color pigment than the push layer. In certainembodiments, the push layer is darker in color than the placebo layer,which helps in identifying the placebo layer side while drilling aorifice in the membrane on the placebo layer side of the multilayercore. In certain embodiments, the push layer includes at least onepigment comprising iron oxide or lake-based colors. In certainembodiments, the pigment is a lake-based color. In certain embodiments,the pigment is an iron oxide pigment, e.g., oxide pigment red, and oxidepigment black. In certain embodiments, the pigment is present in anamount of about 0.5 wt % to about 2 wt % of the push layer.

In certain embodiments, the amount of push layer, based on the totalweight of the uncoated core, can be between about 10 wt % and about 60wt %, between about 20 wt % and about 55 wt %, between about 25 wt % andabout 50 wt %, or between about 30 wt % and about 40 wt %.

Semipermeable Membrane

In certain embodiments, the trilayer tablet core is coated with asemipermeable membrane. In certain embodiments, the semipermeablemembrane is a polymeric film coating containing at least oneorifice/hole/delivery port for drug release. In certain embodiments,size of the orifice must be optimized to control drug release from thedosage form. The size of orifice should not be too large to allow solutediffusion from the orifice into the core, and not too small to buildhydrostatic pressure within the core.

In certain embodiments, the orifice is made via manual or laserdrilling. In certain embodiments, the optimum orifice diameter is lessthan about 2.0 mm. In certain embodiments, the optimum orifice diameteris about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm,about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm,about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm,about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm orany intermediate values therein. In certain embodiments, the optimumorifice diameter is equivalent to the diameter of the top of placebolayer end of the tablet core coated with the semipermeable membrane. Incertain embodiments, it is important that the semipermeable membrane isadequately perforated with an orifice without compromising the integrityof the tablet core.

In certain embodiments, the coating composition and/or coating weightgain of the semipermeable membrane determines the lag time provided bythe composition. In certain embodiments, the coating weight gain of thesemipermeable membrane ranges from about 1 wt % to about 50 wt %, fromabout 5 wt % to about 45 wt %, from about 5 wt % to about 40 wt %, fromabout 5 wt % to about 35 wt %, from about 5 wt % to about 30 wt %, fromabout 5 wt % to about 25 wt %, from about 5 wt % to about 20 wt %, fromabout 5 wt % to about 15 wt %, from about 5 wt % to about 10 wt %, orany intermediate ranges therein, based on the total weight of theuncoated tablet core weight. In certain embodiments, the coating weightgain is about 10 wt %, about 12.5 wt %, or about 15 wt %, based on thetotal weight of the uncoated tablet core.

In certain embodiments, the semipermeable membrane coat over themultilayered tablet core is substantially impermeable to drugs andexcipients present in the programmable osmotic-controlled oralcomposition. In certain embodiments, the semipermeable membrane ispermeable to solvents, e.g., water, GI fluid, and simulated GI fluid. Incertain embodiments, the semipermeable membrane doesn't react withgastric fluid regardless of the pH. In certain embodiments, thesemipermeable membrane maintains the integrity of the composition toprovide constant osmotic pressure during drug delivery. In certainembodiments, the semipermeable membrane comprises one or morepH-independent water-insoluble polymers that are permeable to water andsubstantially impermeable to solutes, e.g., drugs and excipients.Polymers suitable for inclusion in the semipermeable membrane comprisecellulose esters, e.g., cellulose acetate, cellulose diacetate,cellulose triacetate, cellulose propionate, cellulose acetate butyrate,and combinations thereof. In certain embodiments, the semipermeablemembrane comprises cellulose acetate. In certain embodiments, thepermeability of the semipermeable membrane can be enhanced by increasingthe acetyl content in cellulose acetate. In certain embodiments, thesemipermeable membrane comprises cellulose acetate with at least about30% acetyl content. In certain embodiments, the semipermeable membranecomprises cellulose acetate with about 32% acetyl content, about 35%acetyl content, about 38% acetyl content, about 39% acetyl content, orabout 39.8% acetyl content. In certain embodiments, permeability of thesemipermeable membrane is enhanced by addition of water-soluble poreformers to the membrane composition. In certain embodiments, thewater-soluble pore formers comprise, but are not limited to, ofpolyethylene glycol (PEG 400, PEG 1000, PEG 1450, PEG 3350),hydroxypropyl cellulose, polyvinyl pyrolidone (PVP), KOLLIDON® 30,KOLLICOAT® IR, sucrose, glucose, fructose, lactose, mannose, mannitol,sorbitol, methyl cellulose (METHOCEL™ E3, METHOCEL™ E5, METHOCEL™ E6),poloxamers, e.g., poloxamer 188, triethyl citrate, triacetin,hydroxypropyl methylcellulose, polyhydric alcohols such as glycerol, andcombinations thereof. In certain embodiments, the semipermeable membranecomprises cellulose acetate and a pore former comprising polyethyleneglycol. In certain embodiments, the water-insoluble polymer is celluloseacetate and the pore former is polyethylene glycol 3350. In certainembodiments, weight ratio of cellulose acetate to polyethylene glycol isbetween about 80:20 and about 99.5:0.5. In certain embodiments, theratio of cellulose acetate to poloxamer is between about 80:20 and about99.5:0.5. In certain embodiments, weight ratio of cellulose acetate andpore former affects variability in lag time. In certain embodiments,variability in lag time decreases with increasing the amount of poreformer in the membrane. In certain embodiments, lag time decreases withincreasing the amount of pore former in the membrane. In certainembodiments, the weight ratio of cellulose acetate and pore former isoptimized to obtain a desired lag time with minimal variability. Incertain embodiments, the weight ratio of cellulose acetate and poreformer is about 80:20, about 85:15, about 90:10, about 95:5, about 96:4,about 97:3, about 98:2, about 99:1, about 99.5:0.5, or any intermediatevalues therein.

In certain embodiments, the semipermeable membranes include one or moreplasticizers. Plasticizers play a significant role in adjustingflexibility and permeability of the semipermeable membrane. Plasticizerschange the viscoelastic behavior and permeability of the polymer presentin the semipermeable membrane. Plasticizers can convert a hard andbrittle polymer into a softer and more pliable material that has moremechanical strength. Plasticizers used in the semipermeable membranescomprise polyethylene glycols, triethyl citrate, triacetin, diethyltartrate, dibutyl sebacate, and combinations thereof. In certainembodiments, coating solvents used for coating comprise, but are notlimited to, methylene chloride, carbon tetra chloride, acetone,methanol, ethanol, water, and/or any mixtures thereof. In certainembodiments, the coating solvent is a mixture of acetone and water. Incertain embodiments, the acetone:water weight ratio is between 80:20 and95:5. In certain embodiments, the acetone:water weight ratio is about80:20, about 85:15, about 90:10, about 95:5, or any intermediate valuestherein.

In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure include an aesthetic coat over thesemipermeable membrane. In certain embodiments, the aesthetic coatcomprises colors, flavors, and sweeteners. In certain embodiments, theaesthetic coat is the outermost coat comprising OPADRY® II forpigmentation or OPADRY® clear for final glossiness. In certainembodiments, the aesthetic coat further comprises wax to improve flowfor packaging.

Active Pharmaceutical Agents

In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure are suitable for drugs/activepharmaceutical agents comprising any level of aqueous solubilities.

In certain embodiments, drugs suitable for the programmableosmotic-controlled composition of the disclosure include CNS-actingdrugs, cardiovascular-acting drugs, anti-infectives, analgesics,anesthetics, antiarthritics, antiasthmatics, anticonvulsants,antidepressants, antidiabetics, antidiarrheals, antihistamines,anti-inflammatories, antimigraines, antineoplastics, antiparkinsondrugs, antipruritics, antipsychotics, antipyretics, antispasmodics,anticholinergics, sympathomimetics, calcium channel blockers, betablockers, antiarrhythmics, antihypertensives, ACE inhibitors, diuretics,vasodilators, decongestants, hormones, hypnotics, immunosuppresives,parasympathomimetics, prostaglandins, proteins, peptides, sedatives andtranquilizers.

In certain embodiments, drugs suitable for delayed release includeamphetamines, methylphenidate, diltiazem, carbamazepine, metoprolol,oxprenolol, nifedipine, albuterol, phenylpropanolamine, pseudoephedrine,chlorpheniramine maleate, prazosin, doxazosin, verapamil, oxybutyninchloride, isradipine, hydromorphone, paliperidone, modafinil,armodafinil, liothyronine, oseltamivir (Tamiflu), rifamycin, andglipzide.

In certain embodiments, compositions of the disclosure provide chronodrug release and are designed to treat, e.g., diseases in whichbiological rhythm(s) play a vital role in the pathophysiology of suchdiseases to avoid degradation of bioactive agents. In certainembodiments, the compositions of the disclosure are used to treatconditions that require chrono drug release, e.g., attention disorders,asthma, arthritis, congestive heart failure, myocardial infarction,stroke, cancer, peptic ulcer, epilepsy, migraine, pain, etc., whereinthe risk and symptoms of the disease vary predictably over time.

In certain embodiments, chrono release compositions of the disclosureinclude antibiotics such as gentamycin, tobramycin, and amikacin;antihypertensives such as nifedipine, oral nitrates, propranolol, andatenolol; antiepileptic drugs such as valproic acid; anti-inflammatorydrugs such as indomethacin and ketoprofen; anti-asthmatic drugs such astheophylline and beta sympathomimetics; anti-ulcer drugs such asranitidine, cimetidine, and famotidine; anticancer drugs; NSAIDs fortreating arthritis; antihyperlipidemic drugs, such as statins; opioidanalgesics such as tramadol; antimigraine drugs such as sumatriptan;immunosuppressants such as cyclosporine; local anesthetics such aslidocaine, ropivacaine, mepivacaine, and betoxycaine; and generalanesthetics such as barbiturates.

In certain embodiments, immediate release sedatives suitable for theprogrammable osmotic-controlled compositions of the disclosure includeclonidine, diphenhydramine, guanfacine, and/or melatonin.

6.3. Embodiments of the Dosage Form

In certain embodiments, additional programmable osmotic-controlledcompositions containing additional pull layers, IR coatings, etc. arecontemplated. A nonlimiting set of exemplary osmotic-controlledcompositions follows.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure provide delayed extended release of a drug. In certainembodiments, the programmable osmotic-controlled compositions of thedisclosure comprise a multilayer tablet core coated with a semipermeablemembrane containing at least one orifice. In certain embodiments, thetablet core comprises multiple layers in the following order: a placebolayer facing the at least one orifice present in the semipermeablemembrane, a delayed extended release layer containing a drug for delayedextended release, and a push layer, wherein the push layer is away(e.g., furthest away) from the orifice in the semipermeable membrane. Incertain embodiments, the number of orifices in the semipermeablemembrane can be two, three, or four. In certain embodiments, the optimumorifice diameter is about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9mm, about 1.0 mm, about 1.1 mm, or about 1.2 mm. In certain embodiments,the semipermeable membrane facing the top of the placebo layer iscompletely removed to provide an orifice comprising an optimum diameterthat is equivalent to the diameter of the top of the placebo layer endof the multilayer core.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure comprises a combination composition providing animmediate release of a drug, e.g., sedative and a delayed extendedrelease of a different drug, e.g., a stimulant. In certain embodiments,the programmable osmotic-controlled composition of the disclosurecomprises a multilayer tablet core coated with a semipermeable membranecontaining at least one an orifice, and a coating of a sedative forimmediate release, over the semipermeable membrane. In certainembodiments, the tablet core comprises multiple layers in the followingorder: a placebo layer in facing the orifice in the semipermeablemembrane, a delayed extended release layer containing a stimulant, and apush layer, wherein the push layer is away (e.g., furthest away) fromthe orifice in the semipermeable membrane.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure is a combination composition providing an extendedrelease of a drug, e.g., a sedative and a delayed extended release of adifferent drug, e.g., a stimulant. In certain embodiments, theprogrammable osmotic-controlled composition of the disclosure comprisesan IR coat containing a sedative, a seal coat below the IR sedativecoat, an ER coat containing a sedative and below the seal coat, acellulose acetate coat containing an orifice below the ER sedative coat,a “placebo” layer facing the orifice, a delayed extended release layercontaining a stimulant and placed below the placebo layer, and a pushlayer placed below the delayed extended release layer and facing awayfrom the orifice.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure comprises a combination composition providingimmediate release of a drug, e.g., a sedative and a chrono release of adifferent drug, e.g., a stimulant. In certain embodiments, thecomposition comprises a multilayer tablet core coated with asemipermeable membrane containing an orifice, and a coating of a drugfor immediate release over the semipermeable membrane. In certainembodiments, the multilayered tablet core comprises a push layer, and apull layer comprising a placebo layer and an active layer containing astimulant, wherein the active layer comprises an immediate release layerand an extended release layer for providing chrono release of thestimulant. In certain embodiments, the tablet core comprises multiplelayers in the following order: a placebo layer facing the orifice in thesemipermeable membrane, a delayed immediate release layer containing astimulant, a delayed extended release layer containing a stimulant, anda push layer, wherein the push layer is furthest away from the orificein the semipermeable membrane. In certain embodiments, the delayedimmediate release layer and the delayed extended release layer containthe same stimulant.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure comprises a combination composition providing animmediate release of a drug, e.g., a sedative and a delayed chronorelease of a different drug, e.g., a stimulant, wherein the immediaterelease sedative is present as an immediate release layer in the tabletcore. In certain embodiments, the tablet core comprises multiple layersin the following order: an immediate release layer containing a sedativeand facing the orifice in the semipermeable membrane, a placebo layer, adelayed immediate release layer, containing a stimulant, a delayedextended release layer containing a stimulant, and a push layer facingaway from the orifice. In certain embodiments, the delayed immediaterelease layer and the delayed extended release layer contain the samestimulant.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure provides pulsatile release of a drug. In certainembodiments, the composition comprises a multilayer tablet core coatedwith an IR coat comprising a drug, and a coating of a semipermeablemembrane containing an orifice below the IR coat. In certainembodiments, the tablet core comprises multiple layers in the followingorder: a placebo layer facing the orifice in the semipermeable membrane,a delayed immediate release layer comprising the drug, and a push layer,to provide pulsatile release of a drug in two pulses. In certainembodiments, the tablet core comprises a first placebo layer facing theorifice in the semipermeable membrane, a first delayed immediate releaselayer comprising a stimulant, a second placebo layer, a second delayedimmediate release layer, and a push layer, to provide a pulsatilerelease of a drug in three pulses.

In certain embodiments, the programmable osmotic-controlled compositionof the disclosure comprises a combination composition providing animmediate release of a drug, e.g., a sedative and a delayed increasing(gradient) release of a different drug, e.g., a stimulant. In certainembodiments, the composition comprises a multilayer tablet core coatedwith a semipermeable membrane containing an orifice. In certainembodiments, the tablet core comprises multiple layers in the followingorder: a placebo layer facing the orifice in the semipermeable membrane,at least two delayed release layers comprising a stimulant for delayedrelease, and a push layer, wherein the at least two delayed releaselayers release the stimulant over a period of at least two successiveintervals, wherein more stimulant is released in the second intervalcompared to the first interval.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure comprise a multilayer tablet core coated with asemipermeable membrane containing at least one orifice. In certainembodiments, the tablet core comprises multiple layers in the followingorder: a placebo layer facing at least one orifice present in thesemipermeable membrane, a delayed release layer containing a drug, and apush layer, wherein the push layer is away (e.g., furthest away) fromthe orifice in the semipermeable membrane. In certain embodiments, thenumber of orifices in the semipermeable membrane can be two, three, orfour. In certain embodiments, the optimum orifice diameter is about 0.6mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, from about0.6 mm to about 1.2 mm, from about 0.6 mm to about 1.1 mm, from about0.6 mm to about 1.0 mm, from about 0.6 mm to about 0.9 mm, from about0.6 mm to about 0.8 mm, from about 0.7 mm to about 1.2 mm, from about0.8 mm to about 1.2 mm, from about 0.9 mm to about 1.2 mm, from about1.0 mm to about 1.2 mm, from about 1.1 mm to about 1.2 mm, from about0.7 mm to about 1.1 mm, or from about 0.8 mm to about 1.0 mm. In certainembodiments, the semipermeable membrane facing the top of the placebolayer is completely removed to provide an orifice comprising an optimumdiameter that is equivalent to the diameter of the top of the placebolayer end of the multilayer core.

In certain embodiments, the viscosity of the placebo layer, the activelayer, and the push layer, and the drug to polymer ratio in the activelayer determine the release rate of the drug as an immediate releaseportion or an extended release portion. In certain embodiments, animmediate release layer will comprise a higher drug to polymer ratiocompared to an extended release layer containing the same drug and thepolymer.

In certain embodiments, the dosage form of the disclosure comprises animmediate release coat and an extended release coat of the sedative, andthe two coats are separated by a seal coat.

In certain embodiments, the seal coat comprises hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose, hydroxyethyl cellulose, orpovidone. In certain embodiments, the seal coat is present in an amountof between about 1 wt % to about 20 wt %, about 5 wt % to about 20 wt %,or about 5 wt % to about 15 wt % of the tablet core weight without sealcoat.

In certain embodiments, the exemplary clinical situation describedherein involves treatment of ADHD/ADD with an immediate release sedativeand delayed release stimulant therapy.

6.4. Features of the Dosage Form

The present disclosure provides programmable osmotic-controlled oralcompositions that provide delayed controlled release of a drug, and canbe programmed to release drug at a desired time and for a desiredduration, e.g., at a rhythm that matches the requirements for treatmentin a sleep/wake cycle, or at a rhythm that matches the human circadianrhythm of a condition's symptom and/or of the individual being treatedin the application of the therapy, with complete drug recovery. Theosmotic-controlled oral compositions of the disclosure can be programmedto control lag time during the delay period and release drug at adesired rate after the delay period. In certain embodiments, theosmotic-controlled oral compositions are programmed to provide a preciselag time of at least about 4, 5, 6, 7, 8, 9, 10, 11, 12 hours, orintermediate time periods within the range. In certain embodiments, theprogrammable osmotic-controlled oral compositions of the disclosureprovide delayed extended release, delayed chrono release, delayedpulsatile release, and pulsatile release of drugs with various doses andsolubilities, and can be programmed to release drug at a rate thatmatches the human circadian rhythm of a condition's symptom and/or ofthe individual being treated in the application of the therapy. Theprogrammable osmotic-controlled oral compositions of the disclosureprovide pH-independent drug release at an osmotically determined ratefor an extended time period, even as the dosage form transits the GItract and encounters variable hydrodynamic environments of the GI tract,as well as microenvironments with significantly different pH values. Incertain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure provide delayed controlled release of adrug, with minimum variability in lag time in response to varying pH andhydrodynamic conditions of a dissolution medium or the human GI tract.In certain embodiments, the minimal variability in lag time comprisesvariability of not more than 30%, not more than 29%, not more than 28%,not more than 27%, not more than 26%, not more than 25%, not more than24%, not more than 23%, not more than 22%, not more than 21%, not morethan 20%, not more than 19%, not more than 18%, not more than 17%, notmore than 16%, not more than 15%, not more than 14%, not more than 13%,not more than 12%, not more than 11%, not more than 10%, not more than9%, not more than 8%, not more than 7%, not more than 6%, not more than5%, not more than 4%, not more than 3%, not more than 2%, not more than1%, or any intermediate values therein, with variations in pH, presenceor absence of food, gastric motility, or viscosity of dissolutionmedium.

In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure provide an immediate release of a drugand delayed extended release of the same or a different drug. Theprogrammable osmotic-controlled oral compositions of the disclosure cancomprise a multilayer tablet core comprising a drug, wherein the core iscoated with a semipermeable membrane comprising at least one orificeand, optionally, an immediate release drug layer coating/immediaterelease drug layer, comprising a drug for immediate release, over thesemipermeable membrane. In certain embodiments, the immediate releasedrug layer coating includes therapeutically effective doses of two ormore pharmaceutically active ingredients or pharmaceutically effectivesalts thereof. In certain embodiments, the multilayered tablet corecomprises a push layer and a pull layer. In certain embodiments, thepull layer comprises a placebo layer and an active layer. In certainembodiments, the active layer comprises a drug for delayed extendedrelease. In certain embodiments, the drug in the immediate release druglayer coating and the drug in the active layer are different. In certainembodiments, the delayed extended release is a delayed chrono releasecomprising a delayed immediate release and a delayed extended release.In certain embodiments, the placebo layer is facing the orifice.

In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure provide an immediate release of asedative and delayed extended release of methylphenidate hydrochloride.In certain embodiments, the timing of administration of the composition(e.g., in the evening) is titrated to optimize the tolerability andefficacy of the dose, as seen during, e.g., the next morning andthroughout the day. In certain embodiments, the osmotic-controlled oralcompositions of the active agent (e.g., methylphenidate) are programmedto provide drug release as follows: a lag time of at least about, e.g.,6-8 hours, a controlled release comprising about 20% of drug release inabout 1-4 hours after the lag time, and an extended release of the drugwith about 100% drug recovery in about 10-15 hours after the lag time(or about 22 hours from the time of administration of the composition).In certain embodiments, the disclosure provides programmableosmotic-controlled oral compositions of, e.g., methylphenidate that canbe programmed to limit the amount of methylphenidate in plasma to lessthan about 20% of the maximum concentration (C_(max)) during the lagtime to avoid side effects, e.g., insomnia.

In certain embodiments, the disclosure provides programmableosmotic-controlled oral compositions providing pulsatile release of adrug. In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure comprise a multilayered tablet corecomprising layers in the following order: a placebo layer facing theorifice in the semipermeable membrane, an active layer, a (second)placebo layer, an (second) active layer, and a push layer, wherein thepush layer is away (e.g., furthest away) from the orifice in thesemipermeable membrane. In certain embodiments, the pulsatile releasecomprises pulses of drug release separated by a well-defined lagtime(s). In certain embodiments, the pulsatile release is a delayedpulsatile release.

In certain embodiments, the programmable osmotic-controlled oralcompositions of the disclosure are programmed to obtain a desired lagtime by adjusting the composition of the placebo layer and/or the pushlayer, e.g., the amount and/or molecular weight/grade of thepolyethylene oxide polymer (e.g., POLYOX®) in the placebo layer and/orthe push layer, the coating composition of the semipermeable membrane,and/or the coating level of the semipermeable membrane.

In certain embodiments, the amount and/or molecular weight of thePOLYOX® in the placebo layer can affect lag time. In certainembodiments, the placebo layer provides a desired lag time by delayingthe release of the active pharmaceutical ingredient/drug in theenvironment of use. In certain embodiments, the lag time depends uponthe amount/volume of the placebo layer that must be displaced by theexpanding push layer. In certain embodiments, the lag time depends uponthe molecular weight/grade of the POLYOX® (e.g., POLYOX® grade) presentin the placebo layer. In certain embodiments, the lag time increaseswith increasing the molecular weight/grade of the POLYOX® present in theplacebo layer. In certain embodiments, the volume of the placebo layerdepends upon the amount of POLYOX® present in the placebo layer.

In certain embodiments, the average molecular weight of the POLYOX®present in the placebo layer affects lag time. FIG. 14 shows the effectof average molecular weight of the POLYOX® present in the placebo layeron lag time and drug recovery of Tablets 35, 36, and 37, placed in about900 ml of about 0.01N HCl for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. FIG. 14 demonstrates that Tablet 35containing POLYOX® 205 in the placebo layer provides shorter lag timecompared to Tablet 36 containing POLYOX® 1105 in the placebo layer. Thefigure further demonstrates that for Tablets with less coating weightgain (Tablet 35) provide shorter lag time compared with higher coatinglevel (Tablet 36).

In certain embodiments, the average molecular weight of the POLYOX® inthe placebo layer should be at least about 300,000 Da to provide a lagtime of at least about 6 hours. FIG. 23 shows the effect of POLYOX®grade in placebo layer on lag time of Tablets 44, 48, and 49, placed inabout 900 ml of about 0.01N HCl for up to 24 hours, using USP ApparatusII (Sinkers), at 50 rpm and 37° C. Tablet 44 contains POLYOX® 1105 inthe placebo layer; Tablet 48 contains POLYOX® N750 in the placebo layer;and Tablet 49 contains POLYOX® N80 in the placebo layer. The Figuredemonstrates that the average molecular weight of POLYOX® in the placebolayer should be at least about 300K to provide a lag time of at leastabout 6 hours.

In certain embodiments, the lag time increases with increasing placebolayer amount and coating level. FIG. 18 shows effect of polymer amountin the placebo layer and coating weight gain/coating level on lag timeof Tablets 43 and 44, containing a drug:polymer weight ratio of about40:60, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentage drugdissolved is plotted over time (hours). The Figure demonstrates thathigher placebo layer amounts and higher coating level on tabletincreases lag time.

In certain embodiments, the placebo layer amount does not affect lagtime. FIG. 7 shows the effect of the amount of placebo layer amount ondissolution profile of Tablets 20 and 21, placed in about 900 ml ofabout 0.01N HCl, using USP II (sinkers) at about 50 rpm and about 37° C.FIG. 7 demonstrates that compositions containing POLYOX® 1105 in theplacebo layer exhibit higher dissolution rate and higher drug recovery,without affecting lag time, with increasing placebo layer amount.

In certain embodiments, the presence of osmogen in placebo layer hasnegligible effect on lag time and release rate. FIG. 22 shows effect ofsodium chloride in placebo layer on lag time of Tablets 44, 46, and 47,placed in about 900 ml of about 0.01N HCl of tablets for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Tablet 44contains 0% sodium chloride, Tablet 46 contains about 5% sodiumchloride, and Tablet 47 contains about 10% sodium chloride in theplacebo layer, based on the total weight of the placebo layer. TheFigure demonstrates that presence of sodium chloride in placebo layerhas negligible effect on lag time and release rate.

In certain embodiments, the presence of a wicking agent and an osmogenin the placebo layer affects drug recovery. FIG. 25 shows the effect ofthe presence of a wicking agent and an osmogen in the placebo layer onlag time of Tablets 52 and 53, placed in about 900 ml of about 0.01NHCl, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. The Figuredemonstrates that addition of a wicking agent and sodium chloride in theplacebo layer reduces the drug recovery without substantially affectinglag time.

In certain embodiments, the drug:polymer weight ratio in the activelayer affects lag time. FIG. 9 shows the effect of drug:polymer weightratio on lag time and drug recovery of Tablets 23 and 24, placed inabout 900 ml of about 0.01N HCl for up to 24 hours, using USP ApparatusII (Sinkers), at 50 rpm and 37° C. The figure demonstrates thatincreasing drug:polymer weight ratio in the active layer reduces lagtime. The figure further demonstrates that tablets with the drug topolymer weight ratio of about 30:70 provide higher drug recoverycompared to tablets with drug to polymer weight ratio of about 20:80.

In certain embodiments, the presence of an osmogen in the active layerimproves drug recovery. FIG. 10 shows the effect of presence of sodiumchloride in the active layer on dissolution profile of Tablets 25 and26, placed in about 900 ml of about 0.01N HCl using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Tablet 25 contains sodium chloride inthe active layer and Tablet 26 does not contain sodium chloride in theactive layer. The figure demonstrates that Tablet 25 containing NaCl inthe active layer exhibits higher drug recovery compared to Tablet 26containing no amount of sodium chloride in the active layer. Further,FIG. 13 shows the effect of coating weight gain, and presence of sodiumchloride in the active layer, on lag time and drug recovery of Tablets32, 32A, 33, and 34, placed in about 900 ml of about 0.01N HCl for up to24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. TheFigure demonstrates that the tablet with a higher coating level (Tablet32A) exhibits reduced drug recovery and increased lag time compared toTablet 32. The Figure further compares drug recovery between coatedtablets at same coating weight gain, with and without sodium chloride inactive layer. The Figure demonstrates that tablets containing sodiumchloride in active layer exhibit improved drug recovery compared totablets without sodium chloride in the active layer, both tablets at asame coating weight gain. The Figure further shows that a decrease inamount of POLYOX® 205 in placebo layer improves drug recovery.

In certain embodiments, the push layer amount affects lag time and drugrecovery. FIG. 15 shows the effect of push layer amount on lag time ofTablets 38 and 39, placed in about 900 ml of about 0.01N HCl for up to24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. TheFigure demonstrates that for tablets containing POLYOX® 205 in theplacebo layer, the lag time decreases with increase in push layer amountfrom about 17 wt % to about 22 wt %, based on the total weight of theuncoated trilayer tablet.

In certain embodiments, presence of an osmogen in the push layer reduceslag time and improves release rate and drug recovery. FIG. 11 shows theeffect of presence of sodium chloride in the push layer on dissolutionprofile of Tablets 24, 27, 28, and 29, placed in about 900 ml of about0.01N HCl for up to 24 hours, using USP Apparatus II (Sinkers), at 50rpm and 37° C. The figure demonstrates that the presence of sodiumchloride in the push layer reduces lag time and improves release rateand drug recovery at 24 hours. The figure further demonstrates thatincreasing the amount of sodium chloride in the push layer reduces lagtime.

In certain embodiments, the average molecular weight of the POLYOX®present in the push layer affects release rate and drug recovery. FIG.24 shows the effect of POLYOX® grade/average molecular weight in pushlayer on release rate and drug recovery of Tablets 44, 50, and 51,placed in about 900 ml of about 0.01N HCl for up to 24 hours, using USPApparatus II (Sinkers), at 50 rpm and 37° C. The figure compares releaserate and drug recovery in compositions containing POLYOX® WSR 303 (7M),POLYOX® WSR 301 (3M), and POLYOX® WSR Coagulant (5M) in push layer. Thefigure demonstrates that compositions containing POLYOX® N750 in theplacebo layer and POLYOX® WSR 301 in the push layer or compositionscontaining POLYOX® N80 in the placebo layer and POLYOX® WSR Coagulant inthe push layer provide higher drug recovery, compared to compositionscontaining POLYOX® 1105 in the placebo layer and POLYOX® WSR 303 in thepush layer.

In certain embodiments, the ratio of cellulose acetate and polyethyleneglycol in the semipermeable membrane affects lag time and drug recovery.FIG. 12 shows the effect of CA to PEG ratio in the membrane on lag timeand drug recovery of the Tablets 30 and 31, with 15% coating weightgain, placed in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. The Figuredemonstrates that increasing amount of cellulose acetate in the membraneincreases lag time and reduces drug recovery from the membrane coatedtablets.

In certain embodiments, the lag time and release rate of theosmotic-controlled oral compositions of the disclosure does notsubstantially depend upon the pH of the dissolution medium. FIG. 16shows effect of pH on lag time for Tablet 40 with a drug to polymerweight ratio of about 30:70. The figure compares lag time anddissolution profiles of Tablet 40 in about 900 ml of about 0.01N HCl, pH4.5 acetate buffer, and pH 6.8 phosphate buffer, using USP II (sinkers)at 50 rpm and 37° C. The figure demonstrates that the tablets exhibitminimal variability in lag time with variations in pH of the dissolutionmedium. Similarly, FIG. 19 compares the dissolution profiles of Tablet45 in about 0.01 N HCl, in a pH 4.5 acetate buffer, and in a pH 6.8phosphate buffer, using USP II (sinkers) at 50 rpm and 37° C. The figuredemonstrates that the tablets exhibit minimal variability in lag timewith variations in pH of the dissolution medium.

In certain embodiments, the lag time does not change with the viscosityof the dissolution medium. FIG. 20 shows the effect of viscosity of thedissolution medium on lag time of Tablet 45, placed in dissolutionmediums with different viscosities, e.g., with and without HPMC. TheFigure demonstrates there is no substantial change in lag time withchanging viscosity of the dissolution medium.

In certain embodiments, the lag time does not change with changinghydrodynamics of the dissolution medium. FIG. 21 shows the effect ofchanging hydrodynamics of the dissolution medium on lag time of Tablet45, placed in about 900 ml of about 0.01N HCl for up to 24 hours, usingUSP Apparatus II (Sinkers), at 50 rpm and 37° C. Tablet 45 contains adrug:polymer weight ratio of about 40:60. The Figure demonstrates thatthere is no substantial change in lag time with changing hydrodynamicsof the dissolution medium.

In certain embodiments, the size and number of orifices affects %relative standard deviation (% RSD) among tablets. Example 27/Table 27provides % relative standard deviation (% RSD) for Tablet 54A containinga coating with one orifice with 0.6 mm diameter; Tablet 54B containing acoating with two orifices, each with 0.6 mm diameter; and Tablet 54Ccontaining a coating with one orifice with 1.2 mm diameter. The tableshows that Tablet 54B containing two orifices, each with 0.6 mmdiameter; and Tablet 54C containing one orifice with 1.2 mm diametershow significantly reduced % RSD among a set of three tablets, comparedto Tablet 54A containing one orifice with 0.6 mm diameter.

6.5. Methods of Treatment

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure delay the release of a drug and/or release drug at arhythm that matches the human circadian rhythm of a condition's symptomsand/or of the individual being treated in the application of the therapyto optimize therapeutic outcome and minimize side effects. In certainembodiments, the programmable osmotic-controlled compositions of thedisclosure can be used for treating conditions that require release ofdrug following circadian rhythm of the conditions, e.g., central nervoussystem (CNS) disorders, asthma, arthritis, congestive heart failure,myocardial infarction, stroke, cancer, peptic ulcer, narcolepsy,epilepsy, migraine, pain, etc., wherein the risks and symptoms of thedisease vary predictably over time. In certain embodiments, thecomposition can be administered at night (e.g., before bedtime, e.g.,about 8.00 pm) and the drug release is delayed to provide a precise lagtime for about 4 to about 10 hours or longer, followed by an extendedrelease, pulsatile release, or a chrono drug release. In certainembodiments, the compositions of the disclosure exhibit minimalvariability in the lag time.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure provide delayed release of a stimulant used for thetreatment of ADHD/ADD. Treatment of ADHD/ADD with stimulants helps toimprove symptoms of ADHD, as well as to improve self-esteem, cognition,and social and family interactions of the patient. The most commonlyprescribed medications for ADHD include mixed amphetamines andmethylphenidate. These medications have calming and focusing effects onan individual suffering from ADHD. Mixed amphetamines suitable for usein the programmable osmotic-controlled compositions of the disclosureinclude dextroamphetamine, d,l amphetamines, and pharmaceuticallyacceptable salts thereof, for example a mixture of amphetamineaspartate, amphetamine sulfate, dextroamphetamine sulfate, anddextroamphetamine saccharate.

Methylphenidate is a CNS stimulant approved by the FDA in 1955 forhyperactivity. Methylphenidate can be prescribed in a racemic mixture ofdextro and levo conformations or as a pure dextro isomer. The use ofpharmaceutically acceptable salts of methylphenidate, such asmethylphenidate hydrochloride, is also contemplated in the presentdisclosure.

In certain embodiments, the disclosure provides therapeutic compositionsand methods for treatment of attention deficit disorder (ADD), attentiondeficit hyperactive disorder (ADHD), or other attention disorderconditions responsive to central nervous system (CNS) stimulants. Incertain embodiments, the disclosure provides a method of treatingattention disorders in children, comprising administering to a child inneed thereof a programmable osmotic-controlled composition of thedisclosure providing an immediate release of a sedative, and a delayedrelease of a CNS stimulant, e.g., methylphenidate. The immediate releaseof a therapeutic amount of sedative helps the child sleep during thenight, and a delayed and extended release of a therapeutic amount of aCNS stimulant keeps the child alert throughout the active periods of theday, including when the child is waking up. In certain embodiments, therelease of stimulant is delayed for at least about 6 hours followed byan extended release or a chrono release of the stimulant. In certainembodiments, the delayed release of the stimulant is delayed chronorelease. In certain embodiments, the delayed chrono release is delayedimmediate release and a delayed extended release of the stimulant. Incertain embodiments, the sedative is clonidine, diphenhydramine,guanfacine, or melatonin. In certain embodiments, the CNS stimulant ismethylphenidate hydrochloride. In certain embodiments, the compositionis administered before the child goes to bed. In particular, forpediatric patients with ADHD/ADD, once daily doses of suchosmotic-controlled oral compositions of the disclosure at bedtimeproviding an immediate release of a sedative, e.g., clonidine,guanfacine, diphenhydramine, melatonin, for promoting sedation duringnighttime, followed by delayed extended release or chrono release of aCNS stimulant, e.g., methylphenidate, that starts working in the morningand lasts during the daytime, addresses problems of insomnia duringnight, while keeping the child alert and attentive during the day whenthe child is in school or engaged in activities. In certain embodiments,the release of the stimulant is delayed for at least about 4 hours, atleast about 5 hours, at least about 6 hours, at least about 7 hours, atleast about 8 hours, at least about 9 hours, at least about 10 hours, atleast about 11 hours, at least about 12 hours, or any intermediateperiods. The composition provides a suitable lag time such that thesedative is effective during the sleep time of the patient, and thestimulant is effective during the day.

In certain embodiments, the disclosure provides programmableosmotic-controlled methylphenidate compositions providing improvedpatient compliance and convenience. The compositions provide clinicalbenefits of delivering methylphenidate hydrochloride in a delayed andextended manner, independent of drug chemical properties, patientphysiological factors, and food. In certain embodiments, the disclosedcompositions provide a timed, prolonged therapeutic effect when takenonce a day. The programmable osmotic-controlled methylphenidatecompositions of the disclosure provide food-independent delayed releasethat can avoid early morning dosing of methylphenidate hydrochloridestimulant to children suffering from ADHD/ADD. The compositions can beadministered, with or without food, at night, before bedtime, e.g.,about 8:00 pm (although other dosing times are contemplated), andprovide delayed controlled release of a stimulant, e.g.,methylphenidate. In certain embodiments, the osmotic-controlledcompositions of methylphenidate avoid insomnia by limiting residualamount of methylphenidate hydrochloride in plasma to less than about 20%of the maximum concentration (C_(max)) during the lag time (e.g., thedaily lag time).

In certain embodiments, the disclosure provides programmableosmotic-controlled compositions for treating diseases or conditionscomprising attention deficit disorder (ADD), attention deficithyperactive disorder (ADHD), narcolepsy, excessive daytime sleepiness,adrenal insufficiency, major depressive disorder, bipolar disorder,bipolar depression, negative symptoms in schizophrenia, chronic fatigue,or a binge-eating disorder.

In certain embodiments, the disclosure provides programmableosmotic-controlled compositions to improve wakefulness in adult patientswith excessive sleepiness associated with obstructive sleep apnea,narcolepsy, or shift work disorder. In certain embodiments, thedisclosure provides programmable osmotic-controlled compositionscomprising armodafinil. In certain embodiments, the armodafinilcompositions are administered at night to provide delayed extendedrelease of armodafinil throughout the day.

Typically, stimulant-based medications for ADHD/ADD are dosed two hoursprior to beginning an early morning routine, with an onset of treatmenteffect usually about two hours after administration. Such medicationsrequire twice-daily administration and cause compliance issues. Thecompositions of the disclosure avoid the need of early morning dosingthat requires an onset time of about two hours and improve the symptomsof a condition in the early morning and throughout the day. Earlymorning symptom control, including getting the children ready forschool, is a major challenge for parents and caregivers of childrensuffering from ADHD/ADD. The programmable osmotic-controlledcompositions of the disclosure provide a convenient method ofadministration in that a single dose can be taken (typically in theevening prior to going to bed, or at whatever time of the day oneretires for an extended period of sleep) and the release of drug isdelayed for at least about 4 hours, e.g., about 6-12 hours.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure provide delayed release, with precise lag time, ofhydrocortisone for the treatment of endometriosis.

The present disclosure provides compositions that can improve thesymptoms of a condition in the early morning and throughout the day,without the need for early morning dosing that requires an onset time ofabout two hours. The present disclosure provides programmableosmotic-controlled oral compositions comprising drugs that usuallyrequire early morning dosing. Such compositions address the long-feltneed of providing food-independent delayed release that can avoidburdensome early morning dosing of drugs to the patients. Thecompositions of the disclosure provide a desired lag time that isindependent of the presence or absence of food, type of food, pH,gastric emptying, gastric motility, and volume of fluid in the GI tract.The compositions can be administered, with or without food, at night,before bedtime (e.g., at about 8 pm), and provide delayed controlledrelease of the active agents.

In certain embodiments, the methylphenidate/mixed amphetaminecompositions of the disclosure provide an immediate release of asedative, e.g., clonidine, diphenhydramine, guanfacine or melatonin, anda delayed controlled release of a CNS stimulant, e.g., methylphenidateor mixed amphetamine salts. In certain embodiments, the compositions ofthe disclosure do not include any sedative. The compositions can beadministered, with or without food, at night, before bedtime and providea delayed release of the stimulant. In certain embodiments, thecompositions of the disclosure provide minimal variability in lag timein various hydrodynamic conditions and pH (both conditions and regions)of the GI tract. In certain embodiments, the timing of administration istitrated to optimize the tolerability and efficacy the next morning andthroughout the day. In certain embodiments, the compositions of thedisclosure avoid insomnia by limiting the residual amount ofmethylphenidate in plasma to less than about 20 wt % of the maximumconcentration (C_(max)) during the determined/planned lag time. Incertain embodiments, the compositions of the disclosure limit theresidual amount of methylphenidate in plasma to less than about 15 wt %,less than about 10 wt %, less than about 5 wt %, less than about 4 wt %,less than about 3 wt %, less than about 2 wt %, or less than about 1 wt% of the maximum concentration (C_(max)).

In certain embodiments, the disclosure provides programmableosmotic-controlled compositions providing delayed pulsatile release of adrug, e.g., osmotic-controlled pulsatile release compositions.

In certain embodiments, the osmotic-controlled pulsatile releasecompositions of the disclosure contain drugs that undergo rapidfirst-pass metabolism and/or require colonic drug delivery.

In certain embodiments, the compositions of the disclosure provideplasma peak concentration at an optimal time, based on circadian rhythmof a condition, and reduce the number of required doses per day bysaturating the first-pass metabolism.

6.6. Methods of Manufacture

In certain embodiments, the pull layer and the push layer in themultilayer programmable osmotic-controlled compositions of thedisclosure comprise granules made by wet granulation. In certainembodiments, wet granulation comprises mixing of intragranularingredients into a pre-blend, addition of liquid to the pre-blend forwetting of the pre-blend and formation of granules, milling fordeagglomeration of granules, and drying and screening of the resultinggranules.

In certain embodiments, the placebo layer comprises a placebo layerblend comprising placebo layer granules and extragranular excipients. Incertain embodiments, the placebo layer granules comprise a swellablehydrophilic polymer, a binder, an osmogen, a stabilizer, and a colorpigment. In certain embodiments, granules further include a wickingagent. In certain embodiments, glidant and lubricant are present asextragranular excipients in the placebo layer blend. In certainembodiments, the granulating solvent for making granules comprisesalcoholic solvent comprising dehydrated alcohol. In certain embodiments,the granulation solvent comprises a hydroalcoholic solvent comprisingdehydrated alcohol and deionized water in varying ratios. In certainembodiments, the granulation solvent is a hydroalcoholic solventcontaining dehydrated alcohol:water ratio of between about 60:40 andabout 99:1 by weight. In certain embodiments, granules are dried,milled, blended with extragranular excipients, and compressed into theplacebo layer blend. In certain embodiments, the placebo layer is madeby dry granulation/slugging. In certain embodiments, the placebo layeris made by direct compaction

In certain embodiments, active layer blend comprises active layergranules and extragranular excipients. In certain embodiments, theactive layer granules comprise an active agent, a swellable hydrophilicpolymer, a binder, an osmogen, a stabilizer, and a color pigment. Incertain embodiments, granules further include a surfactant and/or awicking agent. In certain embodiments, glidant and lubricant are presentas extragranular excipients in the active layer blend. In certainembodiments, the granulating solvent for making granules comprisesalcoholic solvent comprising dehydrated alcohol. In certain embodiments,the granulation solvent comprises a hydroalcoholic solvent comprisingdehydrated alcohol and deionized water in varying ratios. In certainembodiments, the granulation solvent is a hydroalcoholic solventcontaining dehydrated alcohol:water ratio of between about 60:40 andabout 99:1 by weight. In certain embodiments, granules are dried,milled, blended with extragranular excipients, and compressed into theactive layer blend. In certain embodiments, the placebo layer is made bydry granulation/slugging. In certain embodiments, the placebo layer ismade by direct compaction.

In certain embodiments, the push layer blend comprises push layergranules and extragranular excipients. In certain embodiments, the pushlayer granules comprise a swellable hydrophilic polymer, a binder, anosmogen, a stabilizer, and a color pigment. In certain embodiments, thegranulating solvent for making granules comprises alcoholic solventcomprising dehydrated alcohol. In certain embodiments, the granulationsolvent comprises a hydroalcoholic solvent comprising dehydrated alcoholand deionized water in varying ratios. In certain embodiments, thegranulation solvent is a hydroalcoholic solvent containing dehydratedalcohol:water ratio of between about 60:40 and about 99:1 by weight. Incertain embodiments, granules are dried, milled, blended withextragranular excipients, and compressed into the push layer blend. Incertain embodiments, the push layer is made by dry granulation/slugging.In certain embodiments, the push layer is made by direct compaction.

In certain embodiments, the placebo layer blend, the active layer blend,and the push layer blend are filled into a tablet dye and compressedinto a trilayer tablet core. The resulting tablet core is coated with asemipermeable membrane coat followed by laser drilling of an orifice inthe coating, and, optionally, coating of an immediate release druglayer/coat over the semipermeable membrane layer/coat. In certainembodiments, the semipermeable membrane coat includes a water-solublepore former.

In certain embodiments, the water-soluble pore former is a water-solubleplasticizer, e.g., PEG 400, PEG 1000, PEG 1450, PEG 3350. In certainembodiments, the immediate release layer is further coated with an overcoat. In certain embodiments, there is a seal coat between thesemipermeable membrane and the immediate release drug layer comprisingdrug for immediate release. In certain embodiments, coating solventsused for coating comprise, but are not limited to, methylene chloride,carbon tetra chloride, acetone, methanol, ethanol, water, and/or anymixtures thereof. In certain embodiments, the coating solvent is amixture of acetone and water. In certain embodiments, the acetone:waterweight ratio is between 80:20 and 95:5. In certain embodiments, theacetone:water weight ratio is about 80:20, about 85:15, about 90:10,about 95:5, or any intermediate values therein. In certain embodiments,the solvents used for coating the semipermeable membrane include amixture of acetone and water, wherein the film porosity increases withincreasing water content.

For water-sensitive drugs, wet granulation is performed using organicsolvents including methylene chloride, ethanol, isopropyl alcohol, butylalcohol, ethyl acetate, cyclohexane, and carbon tetrachloride. Incertain embodiments, wet granulation can be low shear, high shear, orfluid bed granulation. In certain embodiments, the fluid bed granulationcomprises top spray granulation or rotor granulation.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure comprising active drugs with low drug loading, goodflow, and compressibility are made by dry granulation comprising rollercompaction or slugging. In such embodiments, it is important to matchparticle size of the drug and the swellable hydrophilic polymer, e.g.POLYOX®. In certain embodiments, compositions containing water-sensitiveactive drugs are made by a dry granulation process.

In certain embodiments, the dry granulation process includes slugging.In certain embodiments, slugging comprises blending of active drug andexcipients into a uniform blend, optional milling of the resulting blendto break down agglomerates and disperse the active drug, compacting theblend into large slugs, milling of the slugs into granules with desiredparticle size, and compressing the granules with extragranularexcipients into tablets.

In certain embodiments, dry granulation includes roller compaction,wherein densification of dry powder comprising active drug andexcipients into a compact is obtained by controlled feeding of thepowder through a set of directly opposed counter rotating rollers.

In certain embodiments, the disclosure provides making a multilayeredtablet core for providing delayed controlled release of a drug. Themultilayered tablet core comprises a push layer and a pull layer. Thepull layer comprises granules made by roller compaction or wetgranulation, and the push layer comprises granules made by directcompaction/slugging. In certain embodiments, the push layer comprisesgranules made by wet granulation. In certain embodiments, the pull layercomprises an active layer and a placebo layer.

In certain embodiments, the trilayer tablet core is coated with asemipermeable membrane. In certain embodiments, the semipermeablemembrane is a polymeric film coating containing at least oneorifice/hole/delivery port for drug release. In certain embodiments,size of the orifice must be optimized to control drug release from thedosage form. The size of orifice should not be too large to allow solutediffusion from the orifice into the core, and not too small to buildhydrostatic pressure within the core.

In certain embodiments, the orifice is made via manual or laserdrilling. In certain embodiments, the optimum orifice diameter is lessthan about 2.0 mm. In certain embodiments, the optimum orifice diameteris about 0.1 mm, about 0.2 mm, about 0.3 mm, about 0.4 mm, about 0.5 mm,about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm,about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm,about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2.0 mm, orany intermediate values therein. In certain embodiments, the optimumorifice diameter is equivalent to the diameter of the top of placebolayer end of the tablet core coated with the semipermeable membrane. Incertain embodiments, it is important that the semipermeable membrane isadequately perforated with an orifice without compromising the integrityof the tablet core.

In certain embodiments, the programmable osmotic-controlled compositionsof the disclosure provide delayed extended release of drugs that areprone to degradation and often have stability and shelf-life problems.Addition of a stabilizing agent, e.g., a pH-adjusting agent, to thecomposition decreases undesired degradation and improves productstability. In certain embodiments, the stabilizing agent comprisessuccinic acid, potassium phosphate, sodium phosphate, fumaric acid,citric acid, tartaric acid, malic acid, hydrochloric acid, asparticacid, glutamic acid, oxalic acid, lactic acid, malonic acid, glycericacid, ascorbic acid, and any combination thereof.

7. EXAMPLES

The following examples illustrate the disclosure in a nonlimitingmanner. Unless indicated to the contrary, the numerical parameters setforth herein can vary depending upon the desired properties sought to beobtained by the present disclosure.

Example 1: Preparation of Delayed Release Methylphenidate TabletCompositions

The present Example provides various formulations for delayed releasemethylphenidate tablets as outlined in Table 1 and Table 2. Sixdifferent tablets were prepared.

TABLE 1 Delayed Extended Release Methylphenidate HCl Tablets Tablet 1Tablet 2 Tablet 3 Composition mg/dose mg/dose mg/dose Placebo layerPolyethylene oxide (POLYOX ® N80) NA 75.00 NA Polyethylene oxide(POLYOX ® 750) 75.00 NA 75.00 Povidone (KOLLIDON ® 30 LP) 8.00 8.00 8.00Succinic acid 3.00 3.00 3.00 Stearic acid 0.90 0.90 0.90 Butylatedhydroxytoluene 0.10 0.10 0.10 Active layer 1 Methylphenidate HCl 10.8010.80 NA Polyethylene oxide (POLYOX ® N80) 54.00 54.00 NA Povidone(KOLLIDON ® 30 LP) 4.00 4.00 NA Succinic acid 1.10 1.10 NA Stearic acid0.05 0.05 NA Butylated hydroxytoluene 0.05 0.05 NA Active layer 2Methylphenidate HCl 43.20 43.20 54.00 Polyethylene oxide (POLYOX ® N80)149.0 149.0 207.0 Povidone (KOLLIDON ® 30 LP) 7.00 7.00 8.00 Succinicacid 3.00 3.00 3.00 Stearic acid 0.75 0.75 0.90 Butylated hydroxytoluene0.05 0.05 0.10 Push Layer Polyethylene oxide (POLYOX ® 303) 135.0 135.0135.0 Povidone (KOLLIDON ® 30 LP) 36.50 36.50 36.50 Sodium chloride 9.159.15 9.15 Stearic acid 0.45 0.45 0.45 Butylated hydroxytoluene 0.10 0.100.10 Red Pigment blend 1.80 1.80 1.80 Functional Coating Layer Celluloseacetate 40.70 40.70 40.70 Polyethylene glycol 3350 0.40 0.40 0.40Acetone* NA NA NA Purified water* NA NA NA Total Weight 584.10 584.10584.10 *Removed during process

TABLE 2 Delayed Extended Release Methylphenidate HCl Tablets Tablet 4Tablet 5 Tablet 6 Composition mg/dose mg/dose mg/dose Placebo layerPolyethylene oxide (POLYOX ® N80) NA 75.00 NA Polyethylene oxide(POLYOX ® 750) 75.00 NA 75.00 Povidone (KOLLIDON ® LP) 8.00 8.00 8.00Succinic acid 3.00 3.00 3.00 Stearic acid 0.90 0.90 0.90 Butylatedhydroxytoluene 0.10 0.10 0.10 Active layer 1 Methylphenidate HCl 10.8010.80 NA Polyethylene oxide (POLYOX ® N80) 37.24 37.24 NA Povidone(KOLLIDON ® 30 LP) 4.00 4.00 NA Succinic acid 1.10 1.10 NA Stearic acid0.05 0.05 NA Butylated hydroxytoluene 0.05 0.05 NA Active layer 2Methylphenidate HCl 43.20 43.20 54.0 Polyethylene oxide (POLYOX ® N80)216.0 216.0 270.0 Povidone (KOLLIDON ® 30 LP) 7.0 7.0 8.0 Succinic acid3.0 3.0 3.0 Stearic acid 0.75 0.75 0.90 Butylated hydroxytoluene 0.050.05 0.10 Push Layer Polyethylene oxide (POLYOX ® 303) 135.0 135.0 135.0Povidone (KOLLIDON ® 30 LP) 36.50 36.50 36.50 Sodium chloride 9.15 9.159.15 Stearic acid 0.45 0.45 0.45 Butylated hydroxytoluene 0.10 0.10 0.10Red Pigment blend 1.80 1.80 1.80 Functional Coating Layer Celluloseacetate 40.70 40.70 40.70 Polyethylene glycol 3350 0.40 0.40 0.40Acetone* NA NA NA Purified water* NA NA NA Total Weight 634.34 634.34647.1 *Removed during process

Tablets 1, 2, 4, and 5 contained two active layers, whereas Tablet 3 andTablet 6 contained only one active layer. Tablets 1 and 2, containeddifferent POLYOX® grade in placebo layer compared to Tablets 4 and 5.The tablets were made according to the following manufacturingprocedure.

Manufacturing Procedure:

Separate blends of placebo layer, active layer 1, active layer 2, andpush layer were made as per Tablets 1-6, using the followingmanufacturing procedure.

1. Preparation of placebo blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed ontopolyethylene oxide taken in a high shear mixer; the resulting granuleswere dried at a temperature of about 40° C. in a forced air oven, andscreened through screen #20; the resulting screened granules were takenin a V-blender containing succinic acid (prescreened through screen #30)and mixed for 7 minutes at 25 RPM, followed by addition of stearic acid(prescreened through screen #30) and further mixing for about 3 minutesat 25 RPM.

2. Preparation of active layer 1 and active layer 2 blend: Povidone andBHT were added to dehydrated alcohol in a suitable stainless-steelcontainer and mixed to obtain a clear solution; the resulting solutionwas sprayed onto a blend of methylphenidate HCl and polyethylene oxidetaken in a high shear mixer; the resulting granules were dried at atemperature of about 40° C. in a forced air oven, and screened throughscreen #20; the resulting screened granules were taken in a V-blendercontaining succinic acid (prescreened through screen #30) and mixed for7 minutes at 25 RPM, followed by addition of stearic acid (prescreenedthrough screen #30) and further mixing for about 3 minutes at 25 RPM.

3. Preparation of push layer blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof polyethylene oxide, sodium chloride, and red pigment blend taken in ahigh shear mixer; the resulting granules were dried at a temperature ofabout 40° C. in a forced air oven, and screened through screen #20; theresulting screened granules were taken in a V-blender containing stearicacid (prescreened through screen #30) and mixed for about 3 minutes at25 RPM.

4. Required amount of each blend was filled into the die, in the orderas per Tables 1 and 2, and then compressed into tetra-layer tabletcompositions as outlined in Tables 1 and 2.

5. Cellulose acetate was added to a stainless-steel container chargedwith acetone and mixed to obtain a clear solution.

6. Polyethylene glycol 3350 was added to the solution from step #5,followed by the addition of water, and mixed for about 30 minutes.

7. The tablets from step #4 were taken in a coating pan and coated withthe solution from step #6 until the target % weight gain is attained,and then cured at a product temperature of 40° C. for one hour.

8. A hole/orifice of about 0.3 mm is drilled into the coating, at theplacebo layer end of the tablet.

Example 2: Preparation of Composition Providing Immediate Release ofClonidine and Delayed Extended Release of Methylphenidate HCl

The present Example provides various formulations for delayed extendedrelease methylphenidate HCL tablets that comprise clonidine HCl IRcoating. The components of the clonidine HCl IR coating are provided inTable 3 below.

TABLE 3 Clonidine HCl IR coating Tablets 7-12 Composition mg/doseClonidine HCl 0.3 Hypromellose (METHOCEL ™ E5 LV) 2.5 Talc 0.5 Ethanol*NA Purified water* NA *Removed during process

The clonidine HCl IR coating is added to Tablets 1-6 of the Example 1according to the procedure detailed below.

Manufacturing Procedure:

1. Hypromellose is added to ethanol taken in a stainless-steel containerand mixed until it is uniformly dispersed. Purified water is slowlyadded and mixed until a clear solution is formed.

2. To the solution from step #1, clonidine HCl is added and mixed untildissolved.

3. Talc is added to the solution from step #2 and mixed until it isuniformly dispersed.

4. Methylphenidate HCl tablets (Tablets 1-6) are taken in a coating panand coated with the dispersion from step #3.

Example 3: Preparation of Delayed Extended Release Mixed AmphetamineTablet Compositions Comprising Two Active Layers

The present Example provides three different delayed extended releasemixed amphetamine tablet compositions. The components of the differenttablets are outlined below in Table 4.

TABLE 4 Mixed Amphetamine Tablet Compositions Tablet 13 Tablet 14 Tablet15 Composition mg/dose mg/dose mg/dose Placebo Layer Polyethylene oxide(POLYOX ® NA 6.750 NA N80) Polyethylene oxide (POLYOX ® 6.750 NA 6.750750) Povidone (KOLLIDON ® 30 LP) 0.720 0.720 0.720 Succinic acid 0.2700.270 0.270 Stearic acid 0.081 0.081 0.081 Butylated hydroxytoluene0.009 0.009 0.009 Active Layer 1 Mixed amphetamine salts (base 1.0001.000 NA equivalence) Polyethylene oxide (POLYOX ® 3.35 3.35 NA N80)Povidone (KOLLIDON ® 30 LP) 0.360 0.360 NA Succinic acid 0.099 0.099 NAStearic acid 0.004 0.004 NA Butylated hydroxy\toluene 0.0045 0.0045 NAActive Layer 2 Total amphetamine base equivalence 4.000 4.000 5.000Polyethylene oxide (POLYOX ® 19.44 19.44 24.3 N80) Povidone (KOLLIDON ®30 LP) 0.630 0.630 0.720 Succinic acid 0.270 0.270 0.270 Stearic acid0.0675 0.0675 0.081 Butylated hydroxytoluene 0.0045 0.0045 0.009 PushLayer Polyethylene oxide (POLYOX ® 12.150 12.150 12.150 303) Povidone(KOLLIDON ® 30 LP) 3.285 3.285 3.285 Sodium Chloride 0.823 0.823 0.823Stearic acid 0.45 0.45 0.45 Butylated hydroxytoluene 0.0405 0.04050.0405 Red Pigment blend 0.162 0.162 0.162 Functional Coating LayerCellulose Acetate 3.663 3.663 3.663 Polyethylene Glycol 3350 0.036 0.0360.036 Acetone* NA NA NA Purified water* NA NA NA Total Weight 57.6757.67 58.819 *Removed during process

Tablets 13 and 15 contain POLYOX® 750 in the placebo layer; and Tablet14 contain POLYOX® N80 in the placebo layer. Tablet 13 and Tablet 14contain two active layers, and Tablet 15 contain one active layer. Thetablets are made according to the following manufacturing procedure.

Manufacturing Procedure:

Tablets 13-15 comprise two active layers, Active layer 1 and Activelayer 2, to provide delayed chrono drug release. Separate blends ofplacebo layer, active layer 1, active layer 2, and push layer are madeas per Tablets 13-15.

Preparation of placebo blend: Povidone and BHT are added to dehydratedalcohol in a suitable stainless-steel container and mixed to obtain aclear solution; the resulting solution is sprayed onto polyethyleneoxide taken in a high shear mixer; the resulting granules are dried at atemperature of about 40° C. in a forced air oven, and screened throughscreen #20; the resulting screened granules were taken in a V-blendercontaining succinic acid (prescreened through screen #30) and mixed for7 minutes at 25 RPM, followed by addition of stearic acid (prescreenedthrough screen #30) and further mixing for about 3 minutes at 25 RPM.

1. Preparation of active layer 1 and active layer 2 blend: Povidone andBHT are added to dehydrated alcohol in a suitable stainless-steelcontainer and mixed to obtain a clear solution; the resulting solutionis sprayed onto a blend of mixed amphetamine base, and polyethyleneoxide taken in a high shear mixer; the resulting granules are dried at atemperature of about 40° C. in a forced air oven, and screened throughscreen #20; the resulting screened granules are taken in a V-blendercontaining succinic acid (prescreened through screen #30) and mixed for7 minutes at 25 RPM, followed by addition of stearic acid (prescreenedthrough screen #30) and further mixing for about 3 minutes at 25 RPM.

2. Preparation of push layer blend: Povidone and BHT are added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution is sprayed onto a blendof polyethylene oxide, sodium chloride, and red pigment blend taken in ahigh shear mixer; the resulting granules are dried at a temperature ofabout 40° C. in a forced air oven, and screened through screen #20; theresulting screened granules are taken in a V-blender containing stearicacid (prescreened through screen #30) and mixed for about 3 minutes at25 RPM.

3. Required amount of each blend is filled into the die, in the order asper Table 4, and then compressed as tetra-layer tablet compositions.

4. Cellulose acetate is added to a stainless-steel container chargedwith acetone and mixed to obtain a clear solution.

5. Polyethylene glycol 3350 is added to the solution from step #5,followed by the addition of water, and mixed for about 30 minutes.

6. The tablets from step #4 are taken in a coating pan and coated withthe solution from step #6 until the target % weight gain is attained andthen cured at a product temperature of 40° C. for one hour.

7. A hole/orifice of about 0.3 mm is drilled into the coating, at theplacebo layer end of the tablet.

Example 4: Preparation of Pulsatile Release Composition Comprising TwoActive Layers Separated by a Placebo Layer

The present Example provides a formulation for pulsatile releasemethylphenidate HCl tablet. The components of the tablet are outlinedbelow in Table 5.

TABLE 5 Pulsatile Release Methylphenidate HCl Tablet Tablet 16Composition mg/dose Placebo Layer Polyethylene oxide (POLYOX ® N80)75.00 Povidone (KOLLIDON ® 30 LP) 8.00 Stearic acid 0.90 Butylatedhydroxytoluene 0.10 Active Layer 1 Methylphenidate HCl 27.00Polyethylene oxide (POLYOX ® N80) 81.00 Povidone (KOLLIDON ® 30 LP) 4.00Stearic acid 0.05 Butylated hydroxytoluene 0.05 Placebo LayerPolyethylene oxide (POLYOX ® N80) 75.00 Povidone (KOLLIDON ® 30 LP) 8.00Stearic acid 0.90 Butylated hydroxytoluene 0.10 Active Layer 2Methylphenidate HCl 27.00 Polyethylene oxide (POLYOX ® N80) 81.0Povidone (KOLLIDON ® 30 LP) 4.00 Stearic acid 0.05 Butylatedhydroxytoluene 0.05 Push Layer Polyethylene oxide (POLYOX ® 303) 135.0Povidone (KOLLIDON ® 30 LP) 36.50 Sodium Chloride 9.15 Stearic acid 0.45Butylated hydroxytoluene 0.10 Red Pigment blend 1.80 Functional CoatingLayer Cellulose Acetate 40.70 Polyethylene Glycol 3350 0.40 Acetone* NAPurified water* NA Total Weight 616.30 *Removed during Process

Tablet 16 contains two placebo layers and two active layers disposedalternately. The composition further includes a push layer and afunctional coating layer. Tablet 16 is made according to the proceduredetailed below.

Manufacturing Procedure:

Separate blends of placebo layers, active layer 1, active layer 2, andpush layer are made as per Tablet 16.

1. Preparation of placebo blend: Povidone and BHT are added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution is sprayed ontopolyethylene oxide taken in a high shear mixer; the resulting granulesare dried at a temperature of about 40° C. in a forced air oven, andscreened through screen #20; the resulting screened granules are takenin a V-blender containing stearic acid (prescreened through screen #30)and mixed for about 3 minutes at 25 RPM.

2. Preparation of active layer 1 and active layer 2 blend: Povidone andBHT are added to dehydrated alcohol in a suitable stainless-steelcontainer and mixed to obtain a clear solution; the resulting solutionis sprayed onto a blend of methylphenidate HCL, and polyethylene oxidetaken in a high shear mixer; the resulting granules are dried at atemperature of about 40° C. in a forced air oven, and screened throughscreen #20; the resulting screened granules are taken in a V-blendercontaining stearic acid (prescreened through screen #30) and mixed forabout 3 minutes at 25 RPM.

3. Preparation of push layer blend: Povidone and BHT are added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution is sprayed onto a blendof polyethylene oxide, sodium chloride, and red pigment blend taken in ahigh shear mixer; the resulting granules are dried at a temperature ofabout 40° C. in a forced air oven, and screened through screen #20; theresulting screened granules are taken in a V-blender containing stearicacid (prescreened through screen #30) and mixed for about 3 minutes at25 RPM.

4. Required amount of each blend is filled into the die, in the order asper Table 5, and then compressed into penta-layer tablet compositions.

5. Cellulose acetate is added to a stainless-steel container chargedwith acetone and mixed to obtain a clear solution.

6. Polyethylene glycol 3350 is added to the solution from step #5,followed by the addition of water, and mixed for about 30 minutes.

7. The tablets from step #4 are taken in a coating pan and coated withthe solution from step #6 until the target % weight gain is attained andthen cured at a product temperature of 40° C. for one hour.

8. A hole/orifice of about 0.3 mm is drilled into the coating, at theplacebo layer end of the tablet.

Example 5 Clonidine HCl IR Coating

The present Example provides a formulation for pulsatile releasemethylphenidate HCl tablet that comprises clonidine HCl IR coating. Thecomponents of the clonidine HCl IR coating are provided in Table 6below.

TABLE 6 Clonidine HCl IR Coating Tablet 17 Composition mg/dose ClonidineHydrochloride 0.3 Hypromellose (METHOCEL E5LV) 2.5 Talc 0.5 Ethanol* NAPurified water* NA *Removed during Process

The clonidine HCl IR coating is added to Tablet 16 of the Example 4according to the procedure detailed below.

Manufacturing Procedure:

1. Hypromellose is added to ethanol taken in a stainless-steel containerand mixed until it is uniformly dispersed. Purified water is slowlyadded and mixed until a clear solution is formed.

2. To the solution from step #1, clonidine hydrochloride is added andmixed until dissolved.

3. Talc is added to the solution from step #2 and mixed until it isuniformly dispersed.

4. The methylphenidate HCl tablets (Tablet 16) are taken in a coatingpan and coated with the dispersion from step #3.

Example 6: Preparation of Delayed Extended Release Methylphenidate HClTablet Compositions Containing One Active Layer

The present Example provides two different delayed extended releasemethylphenidate HCl tablet compositions. The components of the differenttablets are outlined below in Table 7.

TABLE 7 Extended Release Methylphenidate HCl Tablet Compositions Tablet18 Tablet 19 Composition mg/dose mg/dose Placebo Layer Polyethyleneoxide (POLYOX ® WSR 1105) 100.31 100.31 Povidone (KOLLIDON ® 30 LP) 5.225.22 Stearic acid 1.00 1.00 Butylated hydroxytoluene 0.13 0.13 Redpigment blend 0.07 0.07 Cab-O-Sil ® (fumed silica) 0.27 0.27 Dehydratedalcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.00 54.00Polyethylene oxide (POLYOX ® N80) 81.00 81.00 Sodium chloride 10.0010.00 Povidone (KOLLIDON ® 30 LP) 7.60 7.60 Stearic acid 0.90 0.90Butylated hydroxytoluene 0.10 0.10 Dehydrated alcohol* q.s. q.s. PushLayer Polyethylene oxide (POLYOX ® WSR 303) 88.00 88.00 Sodium chloride22.00 22.00 Povidone (KOLLIDON ® 30 LP) 11.50 11.50 Stearic acid 0.500.50 Butylated hydroxytoluene (BHT) 0.20 0.20 Red pigment blend 1.501.50 Cab-O-Sil ® 0.30 0.30 Dehydrated alcohol* q.s. q.s. Total CoreWeight 384.6 384.6 Functional Coating Layer OPADRY ® CA clear (95:5)48.13 57.75 Total Tablet Weight 432.73 442.35 *Removed during process

Tablet 18 and Tablet 19 include different amounts of OPADRY® CA withCA:PEG ratio of about 95:5. The tablets were made according to thefollowing manufacturing procedure.

Manufacturing Procedure

Separate blends of placebo layer, active layer, and push layer were madeas per Tablets 18 and 19.

1. Preparation of placebo blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof polyethylene oxide and red pigment blend taken in a high shear mixer;the resulting granules were dried at a temperature of about 40° C. in aforced air oven, and screened through screen #20; the resulting screenedgranules were taken in a V-blender containing Cab-O-Sil® (prescreenedthrough screen #30) and mixed for about 5 minutes at 25 RPM, followed byaddition of stearic acid and mixing for 3 minutes.

2. Preparation of active layer blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof methylphenidate HCl, polyethylene oxide and sodium chloride taken ina high shear mixer; the resulting granules were dried at a temperatureof about 40° C. in a forced air oven, and screened through screen #20;the resulting screened granules are taken in a V-blender containingstearic acid (prescreened through screen #30) and mixed for about 3minutes at 25 RPM.

3. Preparation of push layer blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof polyethylene oxide, sodium chloride, and red pigment blend taken in ahigh shear mixer; the resulting granules were dried at a temperature ofabout 40° C. in a forced air oven, and screened through screen #20; theresulting screened granules were taken in a V-blender containingCab-O-Sil® (prescreened through screen #30) and mixed for about 5minutes at 25 RPM, followed by addition of stearic acid and furthermixing for 3 minutes.

4. Required amount of each blend (as per Tablets 18 and 19) was filledinto the die and then compressed as tri-layer tablet composition.

5. OPADRY® CA was added to a stainless-steel container charged withacetone and water (about 92:8) and mixed for not less than 60 minutes toobtain a clear solution.

6. The tablets from step #4 were taken in a coating pan and coated withthe solution from step #5 until the target % weight gain was obtainedand cured at a product temperature of 40° C. for one hour.

7. A hole/orifice of about 0.3 mm was drilled into the coating, at theplacebo layer end of the tablet.

Example 7: Dissolution Profiles of Tablets Containing Different Amountsof POLYOX® WSR 1105 in the Placebo Layer

The present Example provides two different delayed extended releasemethylphenidate HCl tablets with various amounts of POLYOX® WSR 1105 inthe placebo layer. The components of the two tablets are outlined belowin Table 8.

TABLE 8 Tablet 20 Tablet 21 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® WSR 150.0 75.0 1105) Povidone (KOLLIDON ®30 LP) 8.0 4.0 Stearic acid 1.6 0.8 Butylated hydroxytoluene 0.20 0.10Dehydrated alcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0Polyethylene oxide (POLYOX ® N80) 135.0 135.0 Povidone (KOLLIDON ® 30LP) 4.0 4.0 Stearic acid 0.90 0.90 Butylated hydroxytoluene 0.10 0.10Dehydrated alcohol* q.s. q.s. Push Layer Polyethylene oxide (POLYOX ®WSR 303) 88.00 88.00 Sodium chloride 22.00 22.00 Povidone (KOLLIDON ® 30LP) 12.0 12.0 Stearic acid 0.50 0.50 Butylated hydroxytoluene (BHT) 0.200.20 Red pigment 1.50 1.50 Dehydrated alcohol* q.s. q.s. Total CoreWeight 478.0 398.1 Functional Coating Layer OPADRY ® CA clear (95:5)71.7 59.7 Total Weight 549.7 457.8 *Removed during process

Tablet 20 contained 150 mg of POLYOX® WSR 1105 in the placebo layer; andTablet 21 contained 75.0 mg of POLYOX® WSR 1105 in the placebo layer.Tablet 20 contained about 34 wt % of placebo layer, based on the totalweight of the uncoated tablet core. Tablet 21 contained about 20 wt % ofplacebo layer, based on the total weight of the uncoated tablet core.Tablets 20 and 21 contained 15 wt % of coating, based on the totalweight of the uncoated tablet core. Trilayer methylphenidate tabletswere made according to the procedure as per Example 5.

Tablets 20 and 21 were tested for dissolution in about 900 ml of about0.01N HCl for up to 24 hours, using USP Apparatus II (Sinkers), at 50rpm and 37° C. Percentage dissolution of the tablets was measured at 2,4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours. FIG. 7 shows theeffect of placebo layer amount on lag time and dissolution profile ofthe tablet. The figure demonstrates that tablets with higher amount ofplacebo layer exhibit higher dissolution rate and higher drug recoverycompared to tablets with lesser amounts of placebo layer. The figurefurther demonstrates that the POLYOX® WSR 1105 amount in the placebolayer, and weight % of placebo layer, based on the total weight of theuncoated tablet core, does not affect lag time.

Example 8: Effect of Average Molecular Weight of POLYOX® Present inPlacebo Layer on Lag Time, Release Rate, and Drug Recovery

The present Example provides two delayed release methylphenidate tabletscomprising different grades of POLYOX® in the placebo layer. Thecomponents of the two tablets are outlined below in Table 9.

TABLE 9 Tablet 22 Tablet 20 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® 205) 150.0 — Polyethylene oxide (POLYOX ®1105) 150.0 Povidone (KOLLIDON ® 30 LP) 8.0 8.0 Stearic acid 1.6 1.6Butylated hydroxytoluene 0.20 0.10 Dehydrated alcohol* q.s. q.s. ActiveLayer Methylphenidate HCl 54.0 54.0 Polyethylene oxide (POLYOX ® N80)135.0 135.0 Povidone (KOLLIDON ® 30 LP) 4.0 4.0 Stearic acid 0.90 0.90Butylated hydroxytoluene 0.10 0.10 Dehydrated alcohol* q.s. q.s. PushLayer Polyethylene oxide (POLYOX ® WSR 303) 88.00 88.00 Sodium chloride22.00 22.00 Povidone (KOLLIDON ® 30 LP) 12.0 12.0 Stearic acid 0.50 0.50Butylated hydroxytoluene (BHT) 0.20 0.20 Red pigment blend 1.50 1.50Dehydrated alcohol* q.s. q.s. Total Core Weight 478.0 478.0 FunctionalCoating Layer OPADRY ® CA clear (95:5) 71.7 71.7 Total Weight 549.7549.7 *Removed during process

Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablets 20 and 22 were tested for dissolution in about900 ml of about 0.01N HCl for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 8 shows the effect of average molecular weight of the POLYOX®,present in the placebo layer, on dissolution rate of the tablet. TheFigure demonstrates an improvement in dissolution rate and reduction indrug recovery, and no change in lag time, with increasing the averagemolecular weight of POLYOX®, present in the placebo layer, from about600K (POLYOX® 205) to about 900K (POLYOX® 1105).

Example 9: Effect of Drug to Polymer Ratio in the Active Layer on LagTime of the Dosage Form

The present Example provides two delayed release methylphenidate tabletscomprising active layers with varying drug to polymer ratios. Thecomponents of the two tablets are outlined below in Table 10.

TABLE 10 Tablet 23 Tablet 24 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® WSR 150.0 150.0 1105) Povidone (KOLLIDON ®30 LP) 8.0 8.0 Stearic acid 1.6 1.6 Butylated hydroxytoluene 0.20 0.20Dehydrated alcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0Polyethylene oxide (POLYOX ® N80) 207.0 (20:80) 135.0 (28:72) Povidone(KOLLIDON ® 30 LP) 4.0 4.0 Stearic acid 0.9 0.9 Butylated hydroxytoluene0.10 0.10 Dehydrated alcohol* q.s. q.s. Push Layer Polyethylene oxide(POLYOX ® WSR 98.00 98.00 303) Sodium chloride 12.00 12.00 Povidone(KOLLIDON ® 30 LP) 12.0 12.0 Stearic acid 0.50 0.50 Butylatedhydroxytoluene (BHT) 0.20 0.20 Red pigment blend 1.50 1.50 Dehydratedalcohol* q.s. q.s. Total core Weight 550.0 478.0 Functional CoatingLayer OPADRY ® CA clear (95:5) 82.5 71.7 Total Weight 632.5 549.7*Removed during process

Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablets 23 and 24 were tested for dissolution in about900 ml of about 0.01N HCl for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 9 shows the effect of drug to polymer ratio in the active layer onlag time of the tablet. The figure demonstrates that increasingdrug:polymer weight ratio in the active layer reduces lag time. Tablet24 with drug to polymer weight ratio of about 30:70 provides a lag timeof about 9 hours, Tablet 23 with a drug to polymer weight ratio of about20:80 provides a lag time of about 10 hours. The figure furtherdemonstrates that tablets with the drug to polymer weight ratio of about30:70 provide higher drug recovery compared to tablets with drug topolymer weight ratio of about 20:80.

Example 10: Effect of Sodium Chloride Amount in the Active Layer on DrugRecovery

The present Example provides two delayed release methylphenidatetablets. Tablet 25 contains sodium chloride in the active layer, whereasTablet 26 does not. The components of the two tablets are outlined belowin Table 11.

TABLE 11 Tablet 25 Tablet 26 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® WSR 1105) 150.0 150.0 Povidone (KOLLIDON ®30 LP) 8.0 8.0 Stearic acid 1.6 1.6 Butylated hydroxytoluene 0.20 0.20Dehydrated alcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0Polyethylene oxide (POLYOX ® N80) 125.0 135.0 Sodium chloride 10.0 —Povidone (KOLLIDON ® 30 LP) 4.0 4.0 Stearic acid 0.9 0.9 Butylatedhydroxytoluene 0.10 0.10 Dehydrated alcohol* q.s. q.s. Push LayerPolyethylene oxide (POLYOX ® WSR 303) 98.00 98.00 Sodium chloride 22.0022.00 Povidone (KOLLIDON ® 30 LP) 12.0 12.0 Stearic acid 0.50 0.50Butylated hydroxytoluene (BHT) 0.20 0.20 Red pigment blend 1.50 1.50Dehydrated alcohol* q.s. q.s. Total Core Weight 488.0 488.0 FunctionalCoating Layer OPADRY ® CA clear (95:5) 71.7 71.7 Total Weight 559.7559.7 *Removed during process

Tablet 25 contained sodium chloride in the active layer; and Tablet 26did not contain any amount of sodium chloride in the active layer.Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablets 25 and 26 were tested for dissolution in about900 ml of about 0.01N HCl for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 10 compares drug recovery from tablets with and without sodiumchloride in active layer. The figure demonstrates that Tablet 25containing NaCl in the active layer exhibits higher drug recoverycompared to Tablet 26 containing no amount of sodium chloride in theactive layer.

Example 11: Effect of Sodium Chloride Amount in the Push Layer on DrugRecovery

The present Example provides four delayed release methylphenidatetablets comprising various amounts of sodium chloride in the push layer.The components of the two tablets are outlined below in Table 12.

TABLE 12 Tablet 24 Tablet 27 Tablet 28 Tablet 29 Composition mg/dosemg/dose mg/dose mg/dose Placebo Layer Polyethylene oxide 150.0 150.0150.0 150.0 (POLYOX ® WSR 1105) Povidone 8.0 8.0 8.0 8.0 (KOLLIDON ® 30LP) Stearic acid 1.6 1.6 1.6 1.6 Butylated 0.20 0.20 0.2 0.2hydroxytoluene Dehydrated alcohol* q.s. q.s. q.s. q.s. Active LayerMethylphenidate HCl 54.0 54.0 54.0 54.0 Polyethylene oxide 135.0 135.0135.0 135.0 (POLYOX ® N80) Povidone 4.0 4.0 4.0 4.0 (KOLLIDON ® 30 LP)Stearic acid 0.9 0.9 0.9 0.9 Butylated 0.10 0.10 0.10 0.10hydroxytoluene Dehydrated alcohol* q.s. q.s. q.s. q.s. Push LayerPolyethylene oxide 98.00 80.00 88.0 110.0 (POLYOX ® WSR 303) Sodiumchloride 12.00 30.00 22.0 NA Povidone 12.0 12.0 12.0 12.0 (KOLLIDON ® 30LP) Stearic acid 0.50 0.50 0.50 0.50 Butylated 0.20 0.20 0.20 0.20hydroxytoluene (BHT) Red pigment blend 1.50 1.50 1.50 1.50 Dehydratedalcohol* q.s. q.s. q.s. q.s. Total Core Weight 478.0 478.0 478.0 478.0Functional Coating Layer OPADRY ® CA clear 71.7 71.7 71.7 71.7 (95:5)Total Weight 549.7 549.7 549.7 549.7 *Removed during process

Tablet 29 did not contain any amount of sodium chloride in the pushlayer; Tablet 24 contained about 10 wt % of sodium chloride, based onthe total weight of the push layer; Tablet 28 contained about 18 wt % ofsodium chloride, based on the total weight of the push layer; and tablet27 contained about 25 wt % of sodium chloride, based on the in pushlayer. Trilayer methylphenidate tablets were made according to theprocedure as per Example 5. Tablets 24, 27, 28, and 29, were tested fordissolution in about 900 ml of about 0.01N HCl for up to 24 hours, usingUSP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentage dissolutionof the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24 hours. FIG. 11 shows the effect of the presence and amount ofsodium chloride in push layer on lag time, release rate, and drugrecovery from the tablet. The figure demonstrates that the presence ofsodium chloride in the push layer reduces lag time and improves releaserate and drug recovery at 24 hours. The figure further demonstrates thatincreasing the amount of sodium chloride in the push layer reduces lagtime.

Example 12: Effect of Membrane Composition on Lag Time and Drug Recovery

The present Example provides two delayed release methylphenidatetablets. Tablet 30 contains OPADRY® CA with CA:PEG ratio of about 95:5in the functional coating layer, while Tablet 31 contains OPADRY® CAwith CA:PEG ratio of about 98:2 in the functional coating layer. Thecomponents of the two tablets are outlined below in Table 13.

TABLE 13 Tablet 30 Tablet 31 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® N205) 150.0 150.0 Povidone (KOLLIDON ® 30LP) 8.0 8.0 Stearic acid 1.6 1.6 Butylated hydroxytoluene 0.20 0.20Dehydrated alcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0Polyethylene oxide (POLYOX ®N80) 135.0 135.0 Povidone (KOLLIDON ® 30 LP)4.0 4.0 Stearic acid 0.9 0.9 Butylated hydroxytoluene 0.10 0.10Dehydrated alcohol* q.s. q.s. Push Layer Polyethylene oxide (POLYOX ®WSR 303) 80.00 80.00 Sodium chloride 30.00 30.00 Povidone (KOLLIDON ® 30LP) 12.0 12.0 Stearic acid 0.50 0.50 Butylated hydroxytoluene (BHT) 0.200.20 Red pigment blend 1.50 1.50 Dehydrated alcohol* q.s. q.s. CoreTablet Weight 478.0 478.0 Functional Coated Layer OPADRY ® CA clear 71.771.7 CA:PEG Ratio 95:5 98:2 Total Weight 549.7 549.7 *Removed duringprocess

Tablet 30 contained OPADRY® CA with CA:PEG ratio of about 95:5 in thefunctional coating layer; and Tablet 31 contained OPADRY® CA with CA:PEGratio of about 98:2 in the functional coating layer. Trilayermethylphenidate tablets were made according to the procedure describedas per Example 5. Tablets 30 and 31 were tested for dissolution in about900 ml of about 0.01N HCl for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 12 shows effect of CA to PEG ratio in the functional coating layeron lag time and drug recovery of the tablets with 15% coating weightgain. The Figure demonstrates that increasing the amount of celluloseacetate in the functional coating layer, at a same coating weight gain,increases lag time and reduces drug recovery from the functional coatedtablets.

Example 13: Effect of Coating Level and Presence of Sodium Chloride inActive Layer on Lag Time and Drug Recovery

The present Example provides four delayed release methylphenidatetablets. The components of the four tablets are outlined below in Table14.

TABLE 14 Tablet 32 Tablet 33 Tablet 34 Tablet 32A Composition mg/dosemg/dose mg/dose mg/dose Placebo Layer Polyethylene oxide 150.0 150.075.0 150.0 (POLYOX ® N205) Povidone 8.0 8.0 4.0 8.0 (KOLLIDON ® 30 LP)Stearic acid 1.6 1.6 0.8 1.6 Butylated 0.20 0.20 0.1 0.2 hydroxytolueneDehydrated alcohol* q.s. q.s. q.s. Active Layer Methylphenidate HCl 54.054.0 54.0 54.0 Polyethylene oxide 125.0 135.0 135.0 125.0 (POLYOX ® N80)Povidone 4.0 4.0 4.0 4.0 (KOLLIDON ® 30 LP) Stearic acid 0.9 0.9 0.9 0.9Sodium chloride 10.0 NA NA 10.0 Butylated 0.10 0.10 0.1 0.10hydroxytoluene Dehydrated alcohol* q.s. q.s. q.s. q.s. Push LayerPolyethylene oxide 88.0 88.0 88.0 88.0 (POLYOX ® WSR 303) Sodiumchloride 22.0 22.0 22.0 22.0 Povidone 12.0 12.0 12.0 12.0 (KOLLIDON ® 30LP) Stearic acid 0.50 0.50 0.50 0.50 Butylated 0.20 0.20 0.20 0.20hydroxytoluene (BHT) Red pigment blend 1.50 1.50 1.5 1.5 Dehydratedalcohol* q.s. q.s. q.s. q.s. Core Tablet Weight 478.0 478.0 398.0 478.0Functional Coating Layer OPADRY ® CA clear 71.7 71.7 59.7 83.65 (95:5)Total Weight 549.0 549.0 457.7 561.65 *Removed during process

Tablet 32 contained 15% coating weight gain of the functional coat layerand Tablet 32A contained 17.5% coating weight gain of the functionalcoat layer, based on the total weight of the uncoated tablets. Tablets32 and 32A contained sodium chloride in the active layer; and Tablets 33and 34 did not contain any amount of sodium chloride in the activelayer. Trilayer methylphenidate tablets were made according to theprocedure as per Example 5. Tablets 32, 32A, the 33, and 34 were testedfor dissolution in about 900 ml of about 0.01N HCl for up to 24 hours,using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentagedissolution of the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, and 24 hours. FIG. 13 shows effect of coating weightgain/coating level of the semipermeable membrane on drug recovery andlag time. The Figure demonstrates that the tablet with a higher coatinglevel (Tablet 32A) exhibits reduced drug recovery and increased lagtime. The Figure further compares drug recovery between coated tabletsat same coating weight gain, with and without sodium chloride in activelayer.

The Figure demonstrates that tablets containing sodium chloride inactive layer exhibit improved drug recovery compared to tablets withoutsodium chloride in the active layer, both tablets at same coating weightgain. The Figure further shows that a decrease in amount of POLYOX® 205present in placebo layer improves drug recovery.

Example 14: Effect of POLYOX® Grade in Placebo Layer, and Amount ofSodium Chloride in Active Layer on Lag Time and Drug Recovery

The present Example provides three delayed release methylphenidatetablets comprising different amounts of sodium chloride in the activelayer and/or different grades of POLYOX® in the placebo layer. Thecomponents of the three tablets are outlined below in Table 15.

TABLE 15 Tablet 35 Tablet 36 Tablet 37 Composition mg/dose mg/dosemg/dose Placebo Layer Polyethylene oxide (POLYOX ® 150.0 150.0 — N205)Polyethylene oxide (POLYOX ® — — 150.0 1105) Povidone (KOLLIDON ® 30 LP)8.0 8.0 8.0 Stearic acid 1.6 1.6 1.6 Butylated hydroxytoluene 0.20 0.200.2 Dehydrated alcohol* q.s. q.s. q.s. Active Layer Methylphenidate HCl54.0 54.0 54.0 Polyethylene oxide (POLYOX ® 187.0 197.0 125.0 N80)Povidone (KOLLIDON ® 30 LP) 4.0 4.0 4.0 Stearic acid 0.9 0.9 0.9 Sodiumchloride 20.0 10.0 10.0 Butylated hydroxytoluene 0.10 0.10 0.1Dehydrated alcohol* q.s. q.s. q.s. Push Layer Polyethylene oxide(POLYOX ® 88.0 88.0 88.0 WSR 303) Sodium chloride 22.0 22.0 22.0Povidone (KOLLIDON ® 30 LP) 12.0 12.0 12.0 Stearic acid 0.50 0.50 0.5Butylated hydroxytoluene (BHT) 0.20 0.20 0.2 Red pigment blend 1.50 1.501.5 Dehydrated alcohol* q.s. q.s. q.s. Core Tablet Weight 550.0 550.0550.0 Functional Coating Layer OPADRY ® CA clear (95:5) 82.5 96.3 82.5Total Weight 632.5 646.3 632.5 *Removed during process

Tablet 35 contained 187.0 mg of POLYOX® N80 and 20 mg of NaCl in theactive layer. Tablet 36 contained 197.0 mg of POLYOX® N80 and 10 mg ofNaCl in the active layer. Tablet 37 contained 125.0 mg of POLYOX® N80and 10 mg of NaCl in the active layer. Tablets 35 and 37 contained 15 wt% coating weight gain and Tablet 36 contained about 17.5 wt % coatingweight gain, based on the total weight of the uncoated trilayer coat.Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablets 35, 36, and 37 were tested for dissolution inabout 900 ml of about 0.01N HCl for up to 24 hours, using USP ApparatusII (Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 14 compares lag time and drug recovery between Tablets 35 and 36containing different amounts of sodium chloride in the active layer anddifferent coating weight gains. Tablets 35 and 36 contained POLYOX® 205®in the placebo layer. Tablet 35, containing about 20 mg of sodiumchloride in the active layer and with about 15 wt % coating weight gain,provides reduced lag time and higher drug recovery compared to tablet36, containing about 10 mg of sodium chloride in the active layer andwith 17.5 wt % coating weight gain. ry. The Figure further comparesdissolution profiles of Tablets 35 and 37 containing POLYOX® 205 in theplacebo layer and about 20 mg of sodium chloride in the active layer;and POLYOX® 1105 in the placebo layer and about 10 mg of sodium chloridein the active layer, respectively. Tablets 35 and 37 contained a coatingweight gain of about 15 wt %, based on the total weight of the uncoatedtrilayer tablet core. Tablet 35 containing POLYOX® 205 and about 20 mgof sodium chloride provides reduced lag time and higher drug recoverycompared to Tablet 37 containing POLYOXO® 1105 and about 10 mg of sodiumchloride.

Example 15: Effect of Push Layer Amount on Lag Time

The present Example provides two delayed release methylphenidate tabletscomprising different amounts of POLYOX® in the push layer. Thecomponents of the two tablets are outlined below in Table 16.

TABLE 16 Tablet 38 Tablet 39 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® N205) 150.0 150.0 Povidone (KOLLIDON ® 30LP) 8.0 8.0 Stearic acid 1.6 1.6 Butylated hydroxytoluene 0.20 0.20Dehydrated alcohol* q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0Polyethylene oxide (POLYOX ® N80) 187.0 187.0 Povidone (KOLLIDON ® 30LP) 4.0 4.0 Stearic acid 0.9 0.9 Butylated hydroxytoluene 0.10 0.10Sodium chloride 20.0 20.0 Dehydrated alcohol* q.s. q.s. Push LayerPolyethylene oxide (POLYOX ® WSR 303) 80.00 62.00 Sodium chloride 22.0015.5 Povidone (KOLLIDON ® 30 LP) 12.0 8.4 Stearic acid 0.50 0.40Butylated hydroxytoluene (BHT) 0.20 0.10 Red pigment blend 1.50 1.10Dehydrated alcohol* q.s. q.s. Core Tablet Weight 542.0 513.3 FunctionalCoating Layer OPADRY ® CA clear (95:5) 82.50 77.1 Total Weight 624.5590.04 *Removed during process

Tablet 38 contained 116.2 mg of push layer (about 22 wt %, based on thetotal weight of the uncoated trilayer tablet core). Tablet 39 contained87.5 mg of push layer (about 17 wt %, based on the total weight of theuncoated trilayer tablet core). Tablets 38 and 39 contained POLYOX® 205in the placebo layer. Trilayer methylphenidate tablets were madeaccording to the procedure described per Example 5. Tablets 38 and 39were tested for dissolution in about 900 ml of about 0.01N HCl for up to24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C.Percentage dissolution of the tablets was measured at 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, and 24 hours. FIG. 15 shows effect of push layeramount on lag time in a compositions with a drug:polymer weight ratio inthe active layer of about 20:80. The Figure demonstrates that fortablets containing POLYOX® 205 in the placebo layer, the lag timedecreases with increase in push layer amount from about 17 wt % to about22 wt %, based on the total weight of the uncoated trilayer tablet core.

Example 16: Effect of pH on Lag Time

The present Example provides a delayed release methylphenidate tabletcomprising a placebo layer, a single active layer, a push layer, and afunctional coating layer. The components of the tablet are outlinedbelow in Table 17.

TABLE 17 Delayed Extended Release Methylphenidate HCl Tablet Tablet 40Composition mg/dose Placebo layer Polyethylene oxide (POLYOX ® N205)150.0 Povidone (KOLLIDON ® 30 LP) 8.0 Stearic acid 1.6 Butylatedhydroxytoluene 0.20 Dehydrated alcohol* q.s. Active layerMethylphenidate HCl 54.0 Polyethylene oxide (POLYOX ® N80) 125.0Povidone (KOLLIDON ® 30 LP) 4.0 Stearic acid 0.9 Butylatedhydroxytoluene 0.10 Sodium chloride 10.0 Dehydrated alcohol* q.s. Pushlayer Polyethylene oxide (POLYOX ® WSR 303) 88.0 Sodium chloride 22.00Povidone (KOLLIDON ® 30 LP) 12.0 Stearic acid 0.50 Butylatedhydroxytoluene (BHT) 0.10 Red pigment blend 1.60 Dehydrated alcohol*q.s. Core Tablet Weight 478.0 Functional Coating Layer OPADRY® CA clear(95:5) 71.7 Total Weight 549.7 *Removed during process

Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablet 40 was tested for dissolution in about 900 ml ofabout 0.01N HCl, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer, forup to 24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C.Percentage dissolution of the tablet was measured at 2, 4, 6, 8, 10, 12,14, 16, 18, 20, 22, and 24 hours. FIG. 16 shows effect of pH on lag timein a tablet with a drug to polymer ratio of about 30:70. The figuredemonstrates that the tablet exhibits minimal variability in lag timewith variations in pH of the dissolution medium.

Example 17: Effect of Push Layer Amount on Lag Time

The present Example provides two delayed release methylphenidate tabletswith different amounts of components in the push layer and thefunctional coating layer. The components of the two tablets are outlinedbelow in Table 18.

TABLE 18 Delayed Extended Release Methylphenidate HCl Tablets Tablet 41Tablet 42 Composition mg/dose mg/dose Placebo Layer Polyethylene oxide(POLYOX ® 1105) 150.0 150.0 Povidone (KOLLIDON ® 30 LP) 8.0 8.0 Stearicacid 1.6 1.6 Butylated hydroxytoluene 0.20 0.20 Dehydrated alcohol* q.s.q.s. Active Layer Methylphenidate HCl 54.0 54.0 Polyethylene oxide(POLYOX ® N80) 81.0 81.0 Povidone (KOLLIDON ® 30 LP) 4.0 4.0 Stearicacid 0.9 0.9 Butylated hydroxytoluene 0.10 0.10 Sodium chloride 10.010.0 Dehydrated alcohol* q.s. q.s. Push Layer Polyethylene oxide(POLYOX ® WSR 303) 71.00 88.00 Sodium chloride 17.7 22.0 Povidone(KOLLIDON ® 30 LP) 12.0 8.4 Stearic acid 0.40 0.50 Butylatedhydroxytoluene (BHT) 0.10 0.10 Red pigment blend 1.3 1.6 Dehydratedalcohol* q.s. q.s. Core Tablet Weight 412.3 430.4 Functional CoatingLayer OPADRY ® CA clear (95:5) 61.5 65.1 Total Weight 473.8 495.5*Removed during process

Tablet 41 contained 108.5 mg of push layer (about 26 wt % of push layer,based on the total weight of the uncoated tablet core) and Tablet 42contained 120.6 mg of push layer (about 28 wt % of push layer, based onthe total weight of the uncoated tablet core). Tablets 41 and 42contained POLYOX® 11'05 in the placebo layer and contained about 15 wt %of the functional coating layer, based on the total weight of theuncoated tablet core. Trilayer methylphenidate tablets were madeaccording to the procedure as per Example 5. Tablets 41 and 42 weretested for dissolution in about 900 ml of about 0.01N HCl for up to 24hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentagedissolution of the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, and 24 hours. FIG. 17 shows effect of push layer amount onlag time in tablets with drug to polymer ratio of about 40:60. Thefigure demonstrates that for tablets containing POLYOX® 1105 in theplacebo layer, an increase in push layer amount, from about 26 wt % toabout 28 wt %, based on the total weight of the uncoated tablet core,improves drug recovery without affecting the lag time.

Example 18: Effect of Coating Level and Placebo Layer Amount on Lag Time

The present Example provides four delayed release methylphenidatetablets. The components of the four tablets are outlined below in Table19.

TABLE 19 Tablet 43 Tablet 44 Tablet 43A Tablet 44A Composition mg/dosemg/dose mg/dose mg/dose Placebo Layer POLYOX ® 1105 150.0 100.0 150.0100.0 Povidone 7.8 5.2 7.8 5.2 (Kollidon ® 30 LP) Stearic acid 1.5 1.01.5 1.0 Butylated 0.20 0.20 0.20 0.20 hydroxytoluene Cab-O-Sil ® 0.3 0.20.3 0.2 Red pigment blend 0.2 0.1 0.2 0.1 Dehydrated alcohol* q.s. q.s.q.s. q.s. Active Layer Methylphenidate 54.0 54.0 54.0 54.0 HCl POLYOX ®N80 81.0 81.0 81.0 81.0 Povidone 8.0 8.0 8.0 8.0 (Kollidon ® 30 LP)Stearic acid 0.9 0.9 0.9 0.9 Cab-O-Sil ® 0.4 0.4 0.4 0.4 Butylated 0.100.10 0.10 0.10 hydroxytoluene Sodium chloride 10.0 10.0 10.0 10.0Dehydrated alcohol* q.s. q.s. q.s. q.s. Push Layer POLYOX ® WSR 88.0088.00 88.00 88.00 303 Sodium chloride 22.0 22.0 22.0 22.0 Povidone 12.012.0 12.0 12.0 (Kollidon ® 30 LP) Stearic acid 0.50 0.50 0.50 0.50Butylated 0.20 0.20 0.20 0.20 hydroxytoluene (BHT) Red pigment blend 1.51.5 1.5 1.5 Cab-O-Sil ® 0.3 0.3 0.3 0.3 Dehydrated alcohol* q.s. q.s.q.s. q.s. Core Tablet Weight 438.9 385.6 438.9 385.6 Functional CoatingLayer Opadry CA clear (95:5) 65.85 57.75 54.87 48.16 Total Weight 493.77433.76 504.75 443.35 *Removed during process

Tablets 43 and 43A contained about 37 wt % of placebo layers, based onthe total weight of the uncoated trilayer tablet core. Tablets 44 and44A contained about 27 wt % of placebo layers, based on the total weightof the uncoated trilayer tablet core. Tablets 43 and 44 contained about12.5% coating weight gain, and Tablets 43A and 44A contained about 15%coating weight gain, based on the total weight of the uncoated trilayertablet core. Trilayer methylphenidate tablets were made according to theprocedure as per Example 5. All tablets were tested for dissolution inabout 900 ml of about 0.01N HCl for up to 24 hours, using USP ApparatusII (Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 18 shows effect of placebo layer amount and coating weightgain/coating level of the tablet, containing a drug:polymer weight ratioof about 40:60, on lag time. The Figure demonstrates that higher placebolayer amount and higher coating level on tablet core increases lag time.

Example 19: Effect of pH and Viscosity of Dissolution Medium on Lag Time

The present Example provides a delayed release methylphenidate tabletcomprising a placebo layer, a single active layer, a push layer and afunctional coating layer. The components of the tablet are outlinedbelow in Table 20.

TABLE 20 Tablet 45 Composition mg/dose Placebo Layer Polyethylene oxide(POLYOX ® 1105) 100.0 Povidone (KOLLIDON ® 30 LP) 5.2 Stearic acid 1.0Butylated hydroxytoluene 0.20 Cab-O-Sil ® 0.3 Dehydrated alcohol* q.s.Active layer Methylphenidate HCl 54.0 Polyethylene oxide (POLYOX ® N80)81.0 Povidone (KOLLIDON ® 30 LP) 8.0 Stearic acid 0.9 Cab-O-Sil ® 0.4Butylated hydroxytoluene 0.10 Sodium chloride 10.0 Dehydrated alcohol*q.s. Push layer Polyethylene oxide (POLYOX ® WSR 303) 88.00 Sodiumchloride 22.0 Povidone (KOLLIDON ® 30 LP) 12.0 Stearic acid 0.50Butylated hydroxytoluene (BHT) 0.20 Red pigment blend 1.5 Cab-O-Sil ®0.3 Dehydrated alcohol* q.s. Core Tablet Weight 385.6 Functional CoatedLayer OPADRY ® CA (95:5) 48.16 Total Weight 433.76 *Removed duringprocess

Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablet 45 was tested for dissolution in about 900 ml ofabout 0.01N HCl, about 900 ml of pH 4.5 acetate buffer, and about 900 mlof pH 6.8 phosphate buffer, for up to 24 hours, using USP Apparatus II(Sinkers), at 50 rpm and 37° C. Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 19 compares dissolution rate of Tablet 45 at pH about 2, pH about4.5, and pH about 6.8. The figure demonstrates that Tablet 45 exhibitsminimal variability in lag time with variations in pH of the dissolutionmedium. FIG. 20 provides dissolution rate of Tablet 45 in dissolutionmediums with different viscosities. The figure demonstrates that Tablet45 exhibits minimal variability in lag time with variations in viscosityof the dissolution medium.

Example 20: Effect of Discrimination Methods on Lag Time

Dissolution profiles of Tablet 45 were compared using USP Apparatus II(Sinkers) at 50 rpm and 37° C. and using USP Apparatus III (Biodis) at25 dpm and 37° C., mimicking effect of stomach shear on dissolution rateof the composition. Tablets 45 were placed individually in about 900 mlof about 0.01N HCl for up to 24 hours, in USP Apparatus II (Sinkers) at50 rpm and 37° C., and in about 250 ml of about 0.01 N HCl for up to 24hours, in USP Apparatus III (Biodis) at 25 dpm and 37° C. Percentagedissolution of the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16,18, 20, 22, and 24 hours using the two methods. FIG. 21 comparesdissolution rate of Tablet 45, containing a drug:polymer weight ratio ofabout 40:60, using the above two methods. The Figure demonstrates thatthere is no substantial change in lag time with changing hydrodynamicsof the dissolution medium.

Example 21: Effect of Sodium Chloride Amount in the Placebo Layer on LagTime and Release Rate

The present Example provides three delayed release methylphenidatetablets comprising different amounts of sodium chloride in the placebolayer. The components of the three tablets are outlined below in Table21.

TABLE 21 Tablet 44 Tablet 46 Tablet 47 Composition mg/dose mg/dosemg/dose Placebo Layer Polyethylene oxide (POLYOX ® 1105) 100.0 100.0100.0 Povidone (KOLLIDON ® 30 LP) 5.2 5.2 5.2 Stearic acid 1.0 1.0 1.0Sodium chloride — 5.33 10.67 Butylated hydroxytoluene 0.20 0.20 0.2Cab-O-Sil ® 0.3 0.2 0.2 Red pigment blend 0.1 0.1 0.1 Dehydratedalcohol* q.s. q.s. q.s. Active Layer Methylphenidate HCl 54.0 54.0 54.0Polyethylene oxide (POLYOX ® N80) 81.0 81.0 81.0 Povidone (KOLLIDON ® 30LP) 8.0 8.0 8.0 Stearic acid 0.9 0.9 0.9 Cab-O-Sil ® 0.4 0.4 0.4Butylated hydroxytoluene 0.10 0.10 0.10 Sodium chloride 10.0 10.0 10.0Dehydrated alcohol* q.s. q.s. q.s Push Layer Polyethylene oxide(POLYOX ® WSR 88.00 88.00 88.00 303) Sodium chloride 22.0 22.0 22.0Povidone (KOLLIDON ® 30 LP) 12.0 12.0 12.0 Stearic acid 0.50 0.50 0.50Butylated hydroxytoluene (BHT) 0.20 0.20 0.20 Red pigment blend 1.5 1.51.5 Cab-O-Sil ® 0.3 0.3 0.3 Dehydrated alcohol* q.s. q.s. q.s. CoreTablet Weight 385.7 390.83 396.27 Functional Coating Layer OPADRY ® CA(95:5) 48.16 48.83 49.49 Total Weight 433.86 439.66 445.76 *Removedduring process

Tablet 44 did not contain any amount of sodium chloride in the placebolayer; Tablet 46 contained 5.33 mg of sodium chloride in the placebolayer; and Tablet 47 contained 10.67 mg of sodium chloride in theplacebo layer. Trilayer methylphenidate tablets were made according tothe procedure as per Example 5. Tablets 44, 46, and 47 were tested fordissolution in about 900 ml of about 0.01N HCl for up to 24 hours, usingUSP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentage dissolutionof the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24 hours. FIG. 22 shows effect of sodium chloride in placebo layeron lag time and release rate. The Figure demonstrates that presence ofsodium chloride in placebo layer has negligible effect on lag time andrelease rate.

Example 22: Effect of POLYOX® Grade in Placebo Layer on Lag Time

The present Example provides three delayed release methylphenidatetablets comprising different grades of POLYOX® in the placebo layer. Thecomponents of the three tablets are outlined below in Table 22.

TABLE 22 Delayed Extended Release Methylphenidate HCl Tablets Tablet 44Tablet 48 Tablet 49 Composition mg/dose mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® 1105) 100.0 — — Polyethylene oxide(POLYOX ® N750) 100.0 Polyethylene oxide (POLYOX ® N80) 100.0 Povidone(KOLLIDON ® 30 LP) 5.2 5.2 5.2 Stearic acid 1.0 1.0 1.0 Sodium chloride— — — Butylated hydroxytoluene 0.20 0.20 0.2 Cab-O-Sil ® 0.3 0.2 0.2 Redpigment blend 0.1 0.1 0.1 Dehydrated alcohol* q.s. q.s. q.s. ActiveLayer Methylphenidate HCl 54.0 54.0 54.0 Polyethylene oxide (POLYOX ®N80) 81.0 81.0 81.0 Povidone (KOLLIDON ® 30 LP) 8.0 8.0 8.0 Stearic acid0.9 0.9 0.9 Cab-O-Sil ® 0.4 0.4 0.4 Butylated hydroxytoluene 0.10 0.100.10 Sodium chloride 10.0 10.0 10.0 Dehydrated alcohol* q.s. q.s. q.sPush Layer Polyethylene oxide (POLYOX ® WSR 88.00 88.00 88.00 303)Sodium chloride 22.0 22.0 22.0 Povidone (KOLLIDON ® 30 LP) 12.0 12.012.0 Stearic acid 0.50 0.50 0.50 Butylated hydroxytoluene (BHT) 0.200.20 0.20 Red pigment blend 1.5 1.5 1.5 Cab-O-Sil ® 0.3 0.3 0.3Dehydrated alcohol* q.s. q.s. q.s. Core Tablet Weight 385.6 385.6 385.6Functional Coating Layer OPADRY ® CA (95:5) 48.16 48.16 48.16 TotalWeight 433.76 433.76 433.76 *Removed during process

Tablet 44 contained POLYOX® 1105 in the placebo layer; Tablet 48contained POLYOX® N750 in the placebo layer; and Tablet 49 containedPOLYOX® N80 in the placebo layer. Trilayer methylphenidate tablets weremade according to the procedure as per Example 5. Tablets 44, 48, and 49were tested for dissolution in about 900 ml of about 0.01N HCl for up to24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C.Percentage dissolution of the tablets was measured at 2, 4, 6, 8, 10,12, 14, 16, 18, 20, 22, and 24 hours. FIG. 23 shows the effect ofPOLYOX® grade in placebo layer on lag time. The Figure compares lag timein compositions containing POLYOX® 80 (200K), POLYOX® 750 (300K), andPOLYOX® 1105 (900K) in placebo layer. The Figure demonstrates that theaverage molecular weight of POLYOX® in the placebo layer should be atleast about 300K to provide a lag time of at least about 6 hours.

Example 23: Effect of POLYOX® Grade in Push Layer on Lag Time

The present Example provides three delayed release methylphenidatetablets comprising different grades of POLYOX® in the push layer. Thecomponents of the three tablets are outlined below in Table 23.

TABLE 23 Tablet 44 Tablet 50 Tablet 51 Composition mg/dose mg/dosemg/dose Placebo Layer Polyethylene oxide (POLYOX ® 1105) 100.0 — —Polyethylene oxide (POLYOX ® N750) 100.0 Polyethylene oxide (POLYOX ®N80) 100.0 Povidone (KOLLIDON ® 30 LP) 5.2 5.2 5.2 Stearic acid 1.0 1.01.0 Butylated hydroxytoluene 0.20 0.20 0.2 Cab-O-Sil ® 0.3 0.2 0.2 Redpigment blend 0.1 0.1 0.1 Dehydrated alcohol* q.s. q.s. q.s. ActiveLayer Methylphenidate HCl 54.0 54.0 54.0 Polyethylene oxide (POLYOX ®N80) 81.0 81.0 81.0 Povidone (KOLLIDON ® 30 LP) 8.0 8.0 8.0 Stearic acid0.9 0.9 0.9 Cab-O-Sil ® 0.4 0.4 0.4 Butylated hydroxytoluene 0.10 0.100.10 Sodium chloride 10.0 10.0 10.0 Dehydrated alcohol* q.s. q.s. q.sPush Layer Polyethylene oxide (POLYOX ® WSR 88.00 — — 303) Polyethyleneoxide (POLYOX ® WSR — 88.0 — 301) Polyethylene oxide (POLYOX ® WSR — —88.0 Coagulant) Sodium chloride 22.0 22.0 22.0 Povidone (KOLLIDON ® 30LP) 12.0 12.0 12.0 Stearic acid 0.50 0.50 0.50 Butylated hydroxytoluene(BHT) 0.20 0.20 0.20 Red pigment blend 1.5 1.5 1.5 Cab-O-Sil ® 0.3 0.30.3 Dehydrated alcohol* q.s. q.s. q.s. Core Tablet Weight 385.6 385.6385.6 Functional Coating Layer OPADRY ® CA (95:5) 48.16 48.16 48.16Total Weight 433.76 433.76 433.76 *Removed during process

Tablet 44 contained POLYOX® 1105 in the placebo layer and POLYOX® WSR303 in the push layer; Tablet 50 contained POLYOX® N750 in the placebolayer and POLYOX® WSR 301 in the push layer; and Tablet 51 containedPOLYOX® N80 in the placebo layer and POLYOX® WSR Coagulant in the pushlayer. Trilayer methylphenidate tablets were made according to theprocedure as per Example 5. Tablets 44, 50, and 51 were tested fordissolution in about 900 ml of about 0.01N HCl for up to 24 hours, usingUSP Apparatus II (Sinkers), at 50 rpm and 37° C. Percentage dissolutionof the tablets was measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22,and 24 hours. FIG. 24 shows the effect of POLYOX® grade/averagemolecular weight in push layer on release rate and drug recovery. Thefigure compares release rate and drug recovery in compositionscontaining POLYOX® WSR 303 (7M), POLYOX® WSR 301 (3M), and POLYOX® WSRCoagulant (5M) in push layer. The figure demonstrates that compositionscontaining POLYOX® N750 in the placebo layer and POLYOX® WSR 301 in thepush layer or compositions containing POLYOX® N80 in the placebo layerand POLYOX® WSR Coagulant in the push layer provide higher drugrecovery, compared to compositions containing POLYOX® 1105 in theplacebo layer and POLYOX® WSR 303 in the push layer.

Example 24: Effect of Presence of a Wicking Agent and Sodium Chloride inPlacebo Layer

The present Example provides two delayed release methylphenidate tabletswith and without sodium chloride, sylloid and croscarmellose sodium inthe placebo layer. The components of the two tablets are outlined belowin Table 24.

TABLE 24 Tablet 52 Tablet 53 Composition mg/dose mg/dose Placebo LayerPolyethylene oxide (POLYOX ® 100.0 100.0 1105) Povidone (KOLLIDON ® 30LP) 5.20 5.20 Stearic acid 1.00 1.0 Butylated hydroxytoluene 0.13 0.13Cab-O-Sil ® 0.27 0.27 Red Pigment blend 0.07 0.07 Croscarmellose sodium4.00 — Sylloid 2.60 — Sodium chloride 19.9 — Dehydrated alcohol* q.s.q.s. Active layer Methylphenidate HCl 54.0 54.0 Polyethylene oxide(POLYOX ® N80) 81.0 36 Povidone (KOLLIDON ® 30 LP) 7.60 5.1 Stearic acid0.90 0.55 Cab-O-Sil ® 0.40 0.28 Butylated hydroxytoluene 0.10 0.07Sodium chloride 10.0 6.70 Dehydrated alcohol* q.s. q.s. Push layerPolyethylene oxide (POLYOX ® 88.0 88.00 WSR Coagulant) Sodium chloride22.0 22.0 Povidone (KOLLIDON ® 30 LP) 12.0 12.0 Stearic acid 0.50 0.50Butylated hydroxytoluene (BHT) 0.20 0.20 Red pigment blend 1.5 1.5Cab-O-Sil ® 0.3 0.30 Dehydrated alcohol* q.s. q.s. Core Tablet Weight411.67 333.87 Functional Coating OPADRY ® CA (95:5) 51.46 41.73 TotalWeight 463.13 375.60 *Removed during process

Trilayer methylphenidate tablets were made according to the procedure asper Example 5. Tablets 52 and 53 were tested for dissolution in about900 ml of about 0.01N HCl, using USP Apparatus II (Sinkers), at 50 rpmand 37° C. Percentage dissolution of the tablet was measured at 2, 4, 6,8, 10, 12, 14, 16, 18, 20, 22, and 24 hours. FIG. 25 comparesdissolution rate of Tablet 52 and Tablet 53. The Figure demonstratesthat addition of a wicking agent and sodium chloride in the placebolayer, reduces drug recovery without affecting lag time.

Example 25: Dissolution in pH 6.8 Buffer, Using USP Apparatus II(Sinkers), Under Low-Volume, Low-RPM (Revolutions Per Minute) Conditionsat 37° C.

The present Example provides four different delayed extended releasemethylphenidate HCl tablet compositions. The components of the differenttablets are outlined below in Table 25.

TABLE 25 Tablet Tablet Tablet Tablet Tablet 54 55 56 57 58 Compositionmg/dose mg/dose mg/dose mg/dose mg/dose Placebo Layer Polyethylene 100.0100.0 80.33 80.33 oxide (POLYOX ® WSR 205) Polyethylene NA NA NA NA100.31 oxide (POLYOX ® WSR 1105) Povidone 5.30 5.30 4.26 4.26 5.22(KOLLIDON ® 30 LP) Sodium chloride 7.60 7.60 6.11 6.11 NA Crospovidone7.40 7.40 5.94 5.94 NA Stearic acid 1.00 1.00 0.80 0.80 1.00 Butylated0.15 0.15 0.12 0.12 0.13 hydroxytoluene Red pigment 0.05 0.05 0.04 0.040.07 blend Cab-O-Sil ® 0.50 0.50 0.40 0.40 0.27 (fumed silica)Dehydrated q.s. q.s. q.s. q.s. q.s. alcohol* Active LayerMethylphenidate 54.00 54.00 54.00 54.00 54.00 HCl Polyethylene 81.0081.00 81.00 81.00 81.00 oxide (POLYOX ® N80) Sodium chloride NA NA NA NA10.00 Succinic acid 10.00 6.3 6.3 6.3 NA Crospovidone 6.30 6.30 6.306.30 NA Povidone 5.00 5.00 5.00 5.00 10.00 (KOLLIDON ® 30 LP) Stearicacid 0.90 0.90 0.90 0.90 0.90 Butylated 0.10 0.10 0.10 0.10 0.10hydroxytoluene Cab-O-Sil ® 0.40 0.40 0.40 0.40 0.40 (fumed silica)Dehydrated q.s. q.s. q.s. q.s. q.s. alcohol* Push Layer Polyethylene NA88.00 70.97 NA 88.00 oxide (POLYOX ® WSR 303) Polyethylene 88.00 NA NA70.97 NA oxide (POLYOX ® WSR Coagulant) Sodium chloride 22.00 22.0017.74 17.74 22.00 Povidone 11.50 11.50 9.28 9.28 11.50 (KOLLIDON ® 30LP) Stearic acid 0.50 0.50 0.40 0.40 0.50 Butylated 0.20 0.20 0.16 0.160.20 hydroxytoluene (BHT) Red pigment 1.50 1.50 1.21 1.21 1.50 blendCab-O-Sil ® 0.30 0.30 0.24 0.24 0.30 Dehydrated q.s. q.s. q.s. q.s. q.s.alcohol* Total Core 403.70 400.00 352.0 352.0 387.4 Weight FunctionalCoating Layer OPADRY ® CA 50.00 35.20 48.425 clear (95:5) OPADRY ® CA40.00 44.00 clear (90:10) Total Tablet 443.07 450.0 387.2 396.0 435.825Weight *Removed during process

Tablets 54-57 contained sodium chloride and crospovidone, as an osmogenand a wicking agent respectively, in the placebo layer; succinic acidand crospovidone, as a stabilizing agent and an osmogen, respectively,in the active layer; and sodium chloride as an osmogen in the pushlayer. Tablet 58 did not contain sodium chloride and crospovidone in theplacebo layer, and succinic acid and crospovidone in the active layer.The tablets were made according to the following manufacturingprocedure.

Manufacturing Procedure

Separate blends of placebo layer, active layer, and push layer were madeas per Tablets 54-58.

1. Preparation of placebo blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof polyethylene oxide, sodium chloride, crospovidone, and red pigmentblend taken in a high shear mixer; the resulting granules were dried ata temperature of about 40° C. in a forced air oven, and screened throughscreen #20; the resulting screened granules were taken in a V-blendercontaining Cab-O-Sil® (prescreened through screen #30) and mixed forabout 5 minutes at 25 RPM, followed by addition of stearic acid andfurther mixing for 3 minutes.

2. Preparation of active layer blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof methylphenidate HCl, polyethylene oxide, succinic acid, andcrospovidone taken in a high shear mixer; the resulting granules weredried at a temperature of about 40° C. in a forced air oven, andscreened through screen #20; the resulting screened granules were takenin a V-blender containing Cab-O-Sil® (prescreened through screen #30)and mixed for about 5 minutes at 25 RPM, followed by addition of stearicacid and further mixing for 3 minutes.

3. Preparation of push layer blend: Povidone and BHT were added todehydrated alcohol in a suitable stainless-steel container and mixed toobtain a clear solution; the resulting solution was sprayed onto a blendof polyethylene oxide, sodium chloride, and red pigment blend taken in ahigh shear mixer; the resulting granules were dried at a temperature ofabout 40° C. in a forced air oven, and screened through screen #20; theresulting screened granules were taken in a V-blender containingCab-O-Sil® (prescreened through screen #30) and mixed for about 5minutes at 25 RPM, followed by addition of stearic acid and furthermixing for 3 minutes.

4. Required amount of each blend (as per Tablets 54-58) was filled intothe die and then compressed as tri-layer tablet composition, as perTable 20.

5. OPADRY® CA was added to a stainless-steel container charged withacetone and water (about 92:8) and mixed for not less than 60 minutes toobtain a clear solution. The tablets from step #4 were taken in acoating pan and coated with the solution from step #5 until the target %weight gain was obtained and cured at a product temperature of 40° C.for one hour.

6. A hole/orifice of about 0.3 mm was drilled into the coating at theplacebo layer end of the tablet.

FIG. 26 provides dissolution profiles of Tablets 54, 57, and 58 in 5 mlof pH 6.8 buffer, using USP Apparatus II (Sinkers), at 5 rpm and 37° C.(low-volume, low-RPM condition). Percentage dissolution of the tabletswas measured at 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 hours.FIG. 26 demonstrates that Tablet 54, with about 10% coating weight gain,based on the total weight of the uncoated tablet core, provides animproved release rate and improved drug recovery compared to Tablets 57and 58, with about 12.5% coating weight gain, based on the total weightof the uncoated tablet core. The figure further demonstrates thatTablets 54 and 57 containing higher amount of pore former (Polyethyleneglycol present in OPADRY® CA clear (90:10)) in the coating layer providefaster drug release compared to Tablet 58 containing less amount of poreformer in OPADRY® CA clear (95:5) in the coating layer. The figure alsodemonstrates that Tablet 58 containing POLYOX® 1105 in the placebo layerand POLYOX® WSR 303 in the push layer provides longer lag time comparedto Tablets 54 and 57 containing POLYOX® 205 in placebo layer and POLYOX®WSR coagulant in the push layer.

Example 26: Oral Bioavailability of Methylphenidate HCl fromOsmotic-Controlled Compositions of the Disclosure

A single dose pharmacokinetic (PK) study was conducted in healthyvolunteers under fed conditions to evaluate and compare the PKperformance of delayed extended release methylphenidate HCl compositionsof the disclosure with a marketed extended release methylphenidate HClproduct (CONCERTA®). An open label, balanced, randomized,three-treatment, six-sequence three-period, single oral dose, three-waycrossover bioequivalence study of Tablets 54 and 57 with CONCERTA®(methylphenidate hydrochloride extended-release tablets), 54 mg, wasconducted in normal, healthy, adult, human subjects under fedconditions.

TABLET 26 Mean ± SD (CV %) (N = 18) Pharmacokinetic Reference ProductParameters (units) Tablet 54 Tablet 57 (54 mg) Cmax  22.0 (44)  17.4(36) 21.0 (35.6) Tmax    12.0 (15.6)  14.2 (23)  9.1 (19.5) AUCO-∞ 219.0(51) 222.0 (40) 296.0 (38) 

The data from this study (Table 26/FIG. 27) demonstrates that Tablet 54provides a lag time of about 7 hours and Cmax of about 22 ng at 12 hourspost administration.

Example 27: Effect of the Number of Orifices on the Placebo Layer End ofthe Functional Coated Tablets on % Variability (Relative StandardDeviation)

Table 27 provides % relative standard deviation (% RSD) for Tablet 54Acontaining a coating with one orifice with 0.6 mm diameter; Tablet 54Bcontaining a coating with two orifices, each with 0.6 mm diameter; andTablet 54C containing a coating with one orifice with 1.2 mm diameter.The tablets were tested for dissolution in 900 ml of 0.01 N HCl for upto 24 hours, using USP Apparatus II (Sinkers), at 50 rpm and 37° C. The% RSD was determined based on variations in dissolution among a set ofthree tablets each, for Tablets 54A, 54B, and 54C, at different timepoints. The table shows that Tablet 54B containing two orifices, eachwith 0.6 mm diameter; and Tablet 54C containing one orifice with 1.2 mmdiameter show significantly reduced % RSD among a set of three tablets,compared to Tablet 54A containing one orifice with 0.6 mm diameter

TABLE 27 Tablet 54A Tablet 54B Tablet 54C (10% coat- (10% coat- (10%coat- 0.6 mm, 1 hole) 0.6 mm, 2 holes) 1.2 mm, 1 hole) % % % Time Dis- %Dis- % Dis- % (hrs) solved RSD solved RSD solved RSD 0 0.0 0.0 0.0 0.00.0 0.0 6 12.0 43.1 10.0 21.5 10.0 14.8 7 21.0 19.6 24.0 15.0 24.0 29.28 33.0 30.2 44.0 13.0 41.0 25.7 9 48.0 36.3 65.0 11.5 58.0 18.9 10 63.030.2 82.0 8.5 73.0 11.7 12 82.0 14.1 97.0 4.6 90.0 3.2

Example 28: Additional Delayed Release Compositions of the Disclosure

The present example provides 4 different delayed extended releasecompositions. Compositions of each of the tablets tested are shown inTable 28.

TABLE 28 Tablet Tablet Tablet Tablet 59 60 61 62 Composition mg/dosemg/dose mg/dose mg/dose Placebo Layer Polyethylene oxide 164.00 164.00164.00 82.00 (POLYOX ® WSR 205) Povidone 8.50 8.50 8.5 4.25 (KOLLIDON ®30 LP) Sodium chloride 25.00 25.00 25.00 15.00 Stearic acid 1.50 1.501.5 1.00 Butylated 0.25 0.25 0.25 0.15 hydroxytoluene Red pigment blend0.10 0.10 0.10 0.05 Cab-O-Sil ® (fumed 0.75 0.75 0.75 0.50 silica)Active Layer Methylphenidate 54.00 54.00 HCl Hydrocortisone 20Armodafinil 50 Polyethylene oxide 81.00 33.67 33.67 33.67 (POLYOX ® N80)Succinic acid 10.00 4.09 10.00 — Crospovidone 6.30 4.09 6.30 4.09Povidone 5.00 3.25 5.00 3.25 (KOLLIDON ® 30 LP) Stearic acid 0.90 0.580.90 0.58 Butylated 0.10 0.06 0.10 0.06 hydroxytoluene Cab-O-Sil ®(fumed 0.40 0.26 0.40 0.26 silica) Push Layer Polyethylene oxide 88.0088.00 88.00 88 (POLYOX ® WSR Coagulant) Sodium chloride 22.00 22.0022.00 22.00 Povidone 11.50 11.50 11.50 11.50 (KOLLIDON ® 30 LP) Stearicacid 0.50 0.50 0.50 0.50 Butylated 0.20 0.20 0.20 0.20 hydroxytoluene(BHT) Red pigment blend 1.50 1.50 1.50 1.50 Cab-O-Sil ® 0.30 0.30 0.300.30 Total Core Weight 481.80 424.10 430.17 288.86 Functional CoatingLayer OPADRY ® CA clear (90:10) 48.18 42.41 43.10 28.86 Total TabletWeight 529.98 466.51 473.27 317.72Trilayer Tablet 59 and Tablet 60 were made by following the procedure asoutlined in Example 25. Trilayer Tablet 61 and Tablet 62 are made byfollowing the procedure as outlined in Example 25.

The present disclosure is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of thedisclosure in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Moreover, thescope of the present disclosure is not intended to be limited to theparticular embodiments of the process, machine, manufacture, compositionof matter, means, methods and steps described in the specification. Asone of ordinary skill in the art will readily appreciate from thedisclosure of the presently disclosed subject matter, processes,machines, manufacture, compositions of matter, means, methods, or steps,presently existing or later to be developed that perform substantiallythe same function or achieve substantially the same result as thecorresponding embodiments described herein can be utilized according tothe presently disclosed subject matter. Accordingly, the appended claimsare intended to include within their scope such processes, machines,manufacture, compositions of matter, means, methods, or steps.

Patents, patent applications, publications, product descriptions, andprotocols are cited throughout this application, the disclosures ofwhich are incorporated herein by reference in their entireties for allpurposes.

What is claimed is:
 1. An osmotic-controlled oral pharmaceuticalcomposition providing delayed release of a drug, the compositioncomprising: a) a multilayer core comprising a placebo layer, an activelayer, and a push layer, wherein: (i) the placebo layer comprises atleast one polyethylene oxide polymer having an average molecular weightof from about 600K Da to about 900K Da, (ii) the active layer comprisesat least one drug, and at least one polyethylene oxide polymer having anaverage molecular weight of less than or equal to 300K Da, (iii) thepush layer comprises at least one osmogen and at least one polyethyleneoxide polymer having an average molecular weight of greater than orequal to 1M Da; and b) a semipermeable membrane, containing at least oneorifice and surrounding the core, wherein the semipermeable membrane isapplied at a coating weight gain of from about 1 wt % to about 50 wt %of the multilayer core without the membrane, wherein the drug isselected from the group consisting of CNS-acting drugs, cardiovasculardrugs, anti-infectives, analgesics, anesthetics, antiarthritics,anticholinergics, anti-asthmatics, antidepressants, antimigraine drugs,antiparkinson drugs, anticonvulsants, armodafinil, modafinil, calciumchannel blockers, beta blockers, decongestant, sedatives,antihypertensives, ACE inhibitors, antidiabetics, and tranquilizers,wherein the layers in the multilayer core are placed in the followingorder: the placebo layer in fluid communication with the at least oneorifice in the semipermeable membrane; the active layer; and the pushlayer facing away from the at least one orifice.
 2. The composition ofclaim 1, wherein the semipermeable membrane comprises a pH-independentwater-insoluble polymer and a water-soluble pore former.
 3. Thecomposition of claim 2, wherein the pH-independent water-insolublepolymer in the semipermeable membrane is selected from the groupconsisting of cellulose acetate, cellulose acetate butyrate, cellulosetriacetate, and combinations thereof.
 4. The composition of claim 2,wherein the water-soluble pore former is selected from the groupconsisting of polyethylene glycol, hydroxypropyl cellulose, polyvinylpyrolidone, polyvinyl acetate, mannitol, and methyl cellulose,poloxamer, triethyl citrate, triacetin, hydroxypropyl methylcellulose,glycerol, and combinations thereof.
 5. The composition of claim 2,wherein the water-soluble pore former is a plasticizer selected from thegroup consisting of polyethylene glycol, triethyl citrate, triacetin,diethyl tartrate, and combinations thereof.
 6. The composition of claim1, wherein the osmogen is selected from the group consisting of sodiumchloride, potassium chloride, potassium sulfate, lithium sulfate, sodiumsulfate, lactose and sucrose combination, lactose and dextrosecombination, sucrose, dextrose, mannitol, dibasic sodium phosphate, andcombinations thereof.
 7. The composition of claim 1, wherein the osmogenis present in an amount of from about 5 wt % to about 40 wt % of thepush layer.
 8. The composition of claim 1, wherein the placebo layer ispresent in an amount of from about 10 wt % to about 60 wt %, based onthe total weight of the multilayer core.
 9. The composition of claim 1,wherein the polyethylene oxide polymer in the placebo layer is presentin an amount of from about 50 wt % to about 99 wt % of the placebolayer.
 10. The composition of claim 1, wherein the active layer furthercomprises a surfactant selected from the group consisting of esters offatty acids; sorbitan fatty acid esters; polyethylene glycol fatty acidesters; polyethylene glycol esters and polyethylene glycol ethers; andpolyethoxylated carboxylic acids, PEG-7 hydrogenated castor oil, andPEG-30 dipolyhydroxystearate; block copolymers based on ethylene oxideand propylene oxide; dioctyl sodium sulfosuccinate (docusate sodium);sodium lauryl sulfate; PEG-32 glyceryl laurate; PEG-32 glycerylpalmitostearate; PEG-8 glyceryl caprylate/caprate; PEG-6 glycerylcaprylate/caprate; macrogol 15 hydroxystearate; polyoxyethylene 20sorbitan monolaurate (polysorbate 20); polyoxyethylene 20 sorbitanmonooleate (polysorbate 80); sorbitan monolaurate; sorbitan monooleate;polyoxyl 40 stearate, and any combinations thereof.
 11. Composition ofclaim 1, wherein the composition when tested for dissolution in about900 ml of a dissolution medium comprising about 0.01N HCl, using USPApparatus II (sinkers) at about 50 rpm and about 37° C., provides a lagtime of at least 4 hours during which the composition releases no morethan 10% of the drug.
 12. An osmotic-controlled oral pharmaceuticalcomposition comprising a multilayer core comprising at least one drugfor delayed release; a semipermeable membrane containing at least oneorifice and surrounding the multilayer core; and an immediate releasedrug layer containing at least one drug for immediate release andsurrounding the semipermeable membrane, wherein the multilayer corecomprises a placebo layer, an active layer, and a push layer, wherein:(i) the placebo layer comprises at least one polyethylene oxide polymerhaving an average molecular weight of from about 600K Da to about 900KDa, (ii) the active layer comprises at least one drug and at least onepolyethylene oxide polymer having an average molecular weight of lessthan or equal to 300K Da, (iii) the push layer comprises at least oneosmogen and at least one polyethylene oxide polymer having an averagemolecular weight of greater than or equal to 1M Da; wherein thesemipermeable membrane is applied at a coating weight gain of from aboutlwt % to about 50 wt % of the multilayer core without the membrane,wherein the layers in the multilayer core are placed in the followingorder: the placebo layer in fluid communication with the at least oneorifice in the semipermeable membrane; the active layer; and the pushlayer facing away from the at least one orifice, wherein the drug fordelayed release is selected from the group consisting of CNS-actingdrugs, cardiovascular drugs, anti-infectives, analgesics, anesthetics,antiarthritics, anticholinergics, anti-asthmatics, antidepressants,antimigraine drugs, antiparkinson drugs, anticonvulsants, armodafinil,modafinil, calcium channel blockers, beta blockers, decongestant,antihypertensives, ACE inhibitors, antidiabetics, and tranquilizers. 13.The composition of claim 12, wherein the drug for immediate release is asedative.
 14. The composition of claim 12, wherein the osmogen ispresent in an amount of from about 5 wt % to about 40 wt % of the pushlayer.
 15. The composition of claim 12, wherein the semipermeablemembrane comprises a pH-independent water-insoluble polymer and awater-soluble pore former.
 16. The composition of claim 12, wherein theplacebo layer is present in an amount of from about 10 wt % to about 60wt %, based on the total weight of the multilayer core.
 17. Thecomposition of claim 12, wherein the polyethylene oxide polymer in theplacebo layer is present in an amount of from about 50 wt % to about 99wt % of the placebo layer.
 18. A method of treating a condition thatrequires release of a drug following circadian rhythm of the condition,the method comprising administering to a subject in need thereof, anosmotic-controlled oral pharmaceutical composition providing delayedrelease of the drug, the composition comprising: a) a multilayer corecomprising a placebo layer, an active layer, and a push layer, wherein:(i) the placebo layer comprises at least one polyethylene oxide polymerhaving an average molecular weight of from about 600K Da to about 900KDa, (ii) the active layer comprises at least one drug, and at least onepolyethylene oxide polymer having an average molecular weight of lessthan or equal to 300K Da, (iii) the push layer comprises at least oneosmogen and at least one polyethylene oxide polymer having an averagemolecular weight of greater than or equal to 1M Da; and b) asemipermeable membrane, containing at least one orifice and surroundingthe core, wherein the semipermeable membrane is applied at a coatingweight gain of from about 1 wt % to about 50 wt % of the multilayer corewithout the membrane, wherein the drug is selected from the groupconsisting of CNS-acting drugs, cardiovascular drugs, anti-infectives,analgesics, anesthetics, antiarthritics, anticholinergics,anti-asthmatics, antidepressants, antimigraine drugs, armodafinil,modafinil, calcium channel blockers, beta blockers, decongestant,antihypertensives, and ACE inhibitors, wherein the layers in themultilayer core are placed in the following order: the placebo layer influid communication with the at least one orifice in the semipermeablemembrane; the active layer; and the push layer facing away from the atleast one orifice.
 19. The method of claim 18, wherein the condition isa disease wherein the risks and symptoms of the disease vary predictablyover time.
 20. The method of claim 18, wherein the disease is selectedfrom the group consisting of attention disorder, asthma, congestiveheart failure, myocardial infarction, stroke cancer, peptic ulcer,epilepsy, migraine, pain, narcolepsy, excessive daytime sleepiness,adrenal insufficiency, major depressive disorder, bipolar disorder,bipolar depression, negative symptoms in schizophrenia, chronic fatigue,or a binge-eating disorder.
 21. The method of claim 18, wherein theplacebo layer is present in an amount of from about 10 wt % to about 60wt %, based on the total weight of the multilayer core.